Evo Devo

2007-12-31T23:59:00.000-08:00

A short form for 'evolutionary development', Evo Devo is a branch of biology that addresses the interface between evolution and development of individuals (ontogeny).

This site will examine genetic regulatory mechanisms that operate during embryologic development, and which have evolved through time to amplify the phenotypic manifestations of genotypic evolution.

"Once seen as distinct, yet complementary disciplines, developmental biology and evolutionary studies have recently merged into an exciting and fruitful relationship. The official union occurred in 1999 when evolutionary developmental biology, or "evo-devo," was granted its own division in the Society for Integrative and Comparative Biology (SICB). It was natural for evolutionary biologists and developmental biologists to find common ground. Evolutionary biologists seek to understand how organisms evolve and change their shape and form. The roots of these changes are found in the developmental mechanisms that control body shape and form. Developmental biologists try to understand how alterations in gene expression and function lead to changes in body shape and pattern. So although SICB only recently validated evo-devo as an independent research area, evo-devo really started over a decade ago when biologists began using an individual organism's developmental gene expression patterns to explain how groups of organisms evolved." Corey S. Goodman, Bridget C. Coughlin The evolution of evo-devo biology PNAS April 25, 2000 Vol. 97, Issue 9, 4424-4425, April 25, 2000 [References]

Genetic expression has traditionally been understood as one gene-one protein. However, it has recently been established that 25,000 human genes can generate about 90,000 proteins. This versatility arises because much genetic expression – production of proteins – is regulated through reversible and transmissable epigenetic mechanisms, which act without an alteration of archival DNA. Alternative splicing, which permits the environment-sensitive, regulated production of multiple polypeptides and proteins from a single gene, increases responsiveness and complexity without a change in the genome. Primate-specific Alu elements, which act as retroposons continue to be replicated and reinserted into the genome, increasing the potential for novel protein combinations.

alternative exons

2007-12-24T12:04:00.000-08:00

Alternative exons are targets of alternative splicing.

Typical features of alternative exons:
1. on average are less than half the size of constitutive exons,
2. include weak 5' and/or 3' splice sites.
3. auxiliary elements aid or prevent the recognition of these exons by binding trans-acting factors depending upon cell type, developmental stage, disease state, or in different environments, and
4. frequency of inclusion of an alternative exon in the mRNA transcript depends on a balance between positive and negative regulation. Enhancer (+) and silencer (-) elements can be found within the alternative exon or the flanking introns (ESE, ISE, ESS, ISS).

Splicing regulation is controlled by multiple elements – for a particular alternative exon these can be different elements, multiple copies of the same element located at different sites, or a combination of both. Different sets of auxiliary elements regulate alternative exons, but those alternative exons that are regulated by the same trans-acting factors share some common elements.

Intronic elements can be distal, but are more often located in the introns adjacent to the alternative exon (exon-intron junction). In some cases, intronic elements overlap with, or are included within, the consensus splice site sequences that are recognized by the basal spliceosomal machinery.

Exon isoforms include:
a. extension/truncation of an exon,
b. cassette exons in which an exon is present in one transcript but absent in an isoform of the transcript,
c. alternating exons that are used in alternative transcripts in a mutually exclusive manner, and d. intron retention in which a nucleotide region is used as an exon in a transcript while it is an intron in an alternative transcript.

Cassette exon, alternating exon, and intron retention can be further characterised as 'complex' or 'simple' depending on whether the 5' or/and 3' flanking exons also undergo modifications. For example, the flanking exon may be extended or truncated, or the exon that flanks a retained intron may be cassetted or alternated.

Alu elements

2007-12-24T12:02:00.000-08:00

Alu elements are about 300 nucleotides in length and include a distinctive sequence that ends in a poly-A tail. The human gene's protein-generating capacity is considerably increased by the presence of Alu elements.

About 5 percent of alternatively spliced exons in the human genome contain an Alu sequence, probably resulting from insertion of an Alu element into an intron of a gene where it would normally be spliced out and so would not have any negative consequence for the primate.

Through mutation, however, an Alu segment can convert an intron into an exon by any alteration in the Alu sequence that generates a new 5' or 3' splice site within the intron, resulting in its recognition by the spliceosome as an exon. (Such mutations usually arise during replication.)

If the new Alu exon is only alternatively spliced-in, the organism can produce a new protein without losing the gene's original function. This results from the original, wild types of mRNA continuing to be synthesized when the Alu exon is spliced-out. Problems arise only when a mutated Alu becomes spliced constitutively such that the Alu exon is always spliced in to all the mRNAs transcripts, with the loss of the original protein.

A single nucleotide polymorphism (point mutation) is sufficient to convert some silent intronic Alu elements into real exons. At present, the human genome contains approximately 500,000 Alu elements located within introns, and 25,000 of those could become new exons by undergoing this single-point mutation. Thus, Alu sequences have the potential to continue to greatly enrich the stock of meaningful genetic information available for producing new human proteins.

Three genetic illnesses have so far been identified as being caused by misplaced Alu sequences: Alport and Sly syndromes and OAT deficiency.

(Sorek et al., Genome Research 2002; Lev-Maor et al., Science 2003; Sorek et al., Molecular Cell 2004). [s]

alternative promoters

2007-12-24T00:08:00.000-08:00

Promoters direct specialized enzymes to the location at which to commence reading the segment of DNA that codes for production of a protein.

Promoters can be divided into two broad categories: those without and those with CpG islands — stretches of DNA containing multiple copies of the nonmethlated dinucleotide CpG, which consists of the nucleotide cytosine (C) followed by guanine (G).

CpG islands comprise about 1 to 2% of the mammalian genome, and about 56% of sequenced human genes have CpG islands near their 5′ ends. This includes all genes that are ubiquitously expressed (housekeeping genes) plus many genes with a tissue-restricted pattern of expression. Promoters are normally located at the upstream edge of the CpG island, such that one or more of the 5′ exons of the gene generally fall within the island region. Although most CpG islands are nonmethylated in all tissues, a small proportion of islands become methylated during development [s].

In adults, single promoters with CpG islands tend to be linked to “housekeeping” genes, whereas single promoters without CpG islands are more often associated with highly regulated biological systems such as the immune and digestive systems.

A greater than expected percentage of mammalian genes have alternative promoters, which are more active during embryological development. Roughly 40-50 % of human and mouse genes have alternative promoters.

Alternative promoters can produce the same protein as single promoters, yet can be active in different tissues or at different times. In other cases, alternative promoters direct the polymerase enzymes to commence reading DNA at different start codons, ultimately resulting in different proteins with different functions.

Alternative promoters can affect gene expression in diverse ways. Production of different mRNA isoforms may be effected directly through different transcription start sites or indirectly through promoter-directed exon inclusion. The resulting transcripts may encode different protein isoforms, or they may vary only in their 5’ untranslated regions, affecting mRNA stability and translation efficiency.

Some genes employ promoters that differ in strength to direct tissue specific expression. Because tight regulation is essential for accurate gene function, loss of regulatory control can have serious disease-causing phenotypic effects such as malignancies resulting from activation of alternative promoters.

Alternative promoters, which confer greater flexibility, are more stable than single promoters over evolutionary time. Mammalian genomes are highly conserved and it is widely believed that gene regulation is largely responsible for the diversity of form and function between species. The higher evolutionary conservation of alternative promoters reflects the higher density of functional elements involved in regulating promoter choice.

Alternative promoters are tightly regulated, in line with their importance in cellular function. Cells with more than one promoter regulate which promoter to use, and when. Alternative promoters are more active during embryonic development.

Alternative Ways of Reading DNA Have Spurred Evolution : Green's studies of promoter function suggest intriguing hypotheses about evolutionary patterns. “The way C. elegans and a lot of other organisms increase their flexibility is simply to make a duplicate copy of a gene and have different regulation for the duplicate,” said Green. “With mammals, one way in which evolution has generated more diversity is to produce different versions of the same gene and allow the cell to regulate expression in multiple tissues. This is a way that evolution gets more bang for its buck, because it gets additional functions for the same gene.”

alternative splicing

2007-12-24T00:04:00.000-08:00

Alternative splicing (AS) is a closely regulated, variable adaptation of the routine RNA modification process of pre-mRNA splicing. Alternative splicing is a form of epigenetic mechanism that enables a single gene to give rise to multiple, differentially spliced versions of a protein, increasing complexity without a change in the genome.

In 1980, a gene called IgM provided the first recognized example of alternative splicing in cells—there were earlier examples in viruses. It has since been demonstrated that cells employ alternative splicing to increase protein diversity toward a variety of biological ends.

An average mammalian gene possesses eight or nine exons—since most human genes undergoing some form of alternative splicing, virtually all of these exons are candidates for elaborate control. The human genome contains 3164.7 million nucleotide bases and only around 25,000 genes, much fewer than the 90,000 proteins that we are estimated to manufacture, and much fewer than prior estimates of 80,000-140,000 expressed sequence tags (ESTs). Human Genome Project

A cell typically splices a single mRNA transcript in multiple ways to generate an assortment of proteins. Alternatively spliced introns tend to lie between those exonal segments of a gene that encode the functional units, or domains, of a protein (ORF).

Alternative splicing can alter the mRNA product in several ways. (click to enlarge image at left)

At the simplest level, an exon can be removed (exon skip), lengthened or shortened (alternative 5'AS or 3'AS splicing). Thus, observed mechanisms of alternative splicing alteration include exon skipping, intron retention, and the use of an alternative splice donor or acceptor site. [r]

Alternative splicing can affect alternative promoters, internal exons, or alternative terminal exons, and generates segments of mRNA variability that shift the reading frame, insert or remove amino acids, or introduce a premature termination codon (Fig. 2). The variable segment within the mRNA results from insertion/deletion, or a mutually exclusive swap. The effects on coding potential are an in-frame insertion or deletion, a reading-frame shift, or introduction of a stop codon. mRNAs containing a stop codon >50 nt upstream of the position of the terminal intron are degraded by nonsense-mediated decay. Therefore, introduction of a premature termination codon into an mRNA by alternative splicing can be a mechanism to down-regulate expression of a gene. Alternative splicing also affects gene expression by removing or inserting regulatory elements controlling mRNA stability (NMD or nonstop decay), translation, or localization.

Exon skipping is the most frequent alternative splicing mechanism known in mammals, constituting about 40% of AS events, and as such is a major contributor to mammalian protein diversity. Exon skipping results in the loss of an exon in the alternatively spliced mRNA.

Alternative donor 5'AS or alternative acceptor 3'AS splicing together contribute to 25% of all AS events conserved between humans and mice (4).

Intron retention is defined by the presence of a transcript-confirmed intron within a transcript-confirmed exon. Intron retention occurs when introns are not spliced out of the RNA transcript, resulting in the intron(s) being retained within the mRNA as part of an exon. This lengthening mechanism the commonest form of alternative splicing in plants and lower multicellular organisms.

Regulation of AS:
Alternative splicing depends upon a splice-site and nearby enhancer and repressor sequences—short segments of RNA that couple with regulatory proteins. It has been estimated that the splicing of a single exon may be promoted by at least three to seven enhancer sequences.

As a result of alternate splicing, mutations that alter a splice site or a nearby regulatory sequence can have subtle effects by shifting the ratio of the resulting proteins without entirely eliminating any form.

Regulation of alternative splicing is often temporal or tissue-specific, generating different protein isoforms in different developmental states or different tissues. At the level of the organism, specific isoforms are known to be produced as a consequence of regulation by extracellular signaling mechanisms. Alternative splicing can allow one gene to generate different proteins in different tissues, providing the diversity encoded within genomes that are smaller than would be expected from gene expression by the organism. Many highly specialized brain proteins arise from differential splicing of genes that are also expressed in other tissues. Cells can even modify splicing in response to changing conditions, and not only can alternative splicing tweak the structure of a single protein, but it may also be a means of regulating entire pathways.

Recent bioinformatics studies have demonstrated that AS-prone exons can be distinguished from constitutively spliced exons by several features(1).
1. Divisibility by three of the exon length, which is likely to ensure the preservation of the reading frame in the mRNA (3).
2. Evolutionary conservation of intronic sequences flanking AS exons (3–8). Though not yet fully understood, the unusually high conservation of the introns that surround AS exons suggests the presence of cis-regulatory elements with regulatory proteins (5).

Alternative splicing is controlled by the binding of trans-acting protein factors to cis-acting sequences within the pre-mRNA, which result in differential use of splice sites. Since the splice sites do not contain enough information to explain the complex regulation of AS, this fine-tuned mechanism is achieved by multiple weak signals across the exons and introns which are recognized by an extensive number of different proteins (2). Many such alternative-binding sequences have been identified and are grouped as either enhancer or suppressor elements. These elements are typically short (8-10 nucleotides) and are less conserved than the splice sites at exon-intron junctions. The elements are either intronic or exonic, and either enhancers or silencers depending upon whether they increase or decrease splicing – ISE, ISS, ESE, ESS.

Members of the SR (serine rich) splicing factors control alternative splice site recognition by binding to the splicing enhancer and inhibitor elements (ESE, ESS, ISE, ISS). The SR proteins interact with the pre-mRNA substrate and with snRNP proteins (small nuclear ribonucleoproteins , pronounced 'snurps'). The role of SR splicing factors in regulating splice site selection is believed to occur in arginine-serine (RS) domain dependent and RS domain independent mechanisms.

animation of alternative splicing if this link does not work then click on figure 1 of alternative splicing link : life cycle of an mRNA ~ click on Quicktime Q :HHMI Feature Article on Alternative Splicing : Artist's conception of AS Controlling the Synapse — 49 Proteins at a Time : The Alternative Splicing Website : Alternative Splicing DB (ASDB) : DNA-RNA-ProteinNational Center for Biotechnology Information

alternative 3' splicing

2007-12-24T00:03:00.000-08:00

AS can also be attained by altering the position of the splice acceptor, alternative 3' splice site (3'AS). Together with alternative donor 5' splice site (5'AS), 3'AS contributes 25% of all AS events conserved between humans and mice (4).

"Recently, Hiller et al. (9) reported a widespread occurrence of a NAGNAG 3' acceptor splice site motif in the human genome. The NAGNAG motif includes two 3' splice site motifs in tandem and thus has the potential of producing mRNA isoforms which differ by a 3 nt sequence (NAG). Based on their analysis, Hiller et al. (9) suggested that the NAGNAG motif, which can insert or delete a single amino acid in the protein, is present in 30% of human genes and is functional in at least 5% of the genes. In addition it has been observed that alternative spliced isoforms, resulting from the NAGNAG motif are differentially expressed in human and mouse tissues (9,10).

...findings suggest that the selection of an acceptor site (3'AS) depends on the sequence environment, and can be altered by subtle changes such as point mutations. This is consistent with other studies showing that the pattern of AS can be altered by mutations in exonic splicing enhancer sites (ESEs) and exonic splicing silencer [sic] sites (ESSs) (16).

... by itself, the NAGNAG motif is not sufficient for AS. Nevertheless, analysis of a subset of the NAGNAG sites confirmed by expressed sequence tag (EST) data to be alternatively spliced shows that they encompass several characteristics of other known AS events. Comparison between the constitutively and alternatively spliced NAGNAG sites revealed that they differ principally by three major properties: (i) the sequence and evolutionary conservation of the NAGNAG motif, (ii) the conservation of intron sequences flanking the NAGNAG site, and (iii) the abundance of known cis-regulatory elements in the neighboring regions of the 3' splice sites. " [Alternative splicing regulation at tandem 3' splice sites]

Regulation of alternative 3' splice site selection by constitutive splicing factors.
Polypyrimidine tract binding protein (PTB) was found to inhibit the splicing of introns containing a strong binding site for this factor. However, the inhibitory effect of PTB could be partially reversed if pre-mRNAs were preincubated with U2 auxiliary factor (U2AF) prior to splicing in PTB-supplemented extracts. For alpha-tropomyosin, regulation of splicing by PTB and U2AF primarily affected the joining of exons 1-3 with no dramatic increases in 1-2 splicing being detected. Preincubation of pre-mRNAs with SR proteins led to small increases in 1-2 splicing. However, if pre-mRNAs were preincubated with SR proteins followed by splicing in PTB-supplemented extracts, there was a nearly complete reversal of the normal 1-2 to 1-3 splicing ratios. Thus, multiple pairwise, and sometimes antagonizing, interactions between constitutive pre-mRNA splicing factors and the pre-mRNA can regulate 3' splice site selection.
Lin CH, Patton JG. Regulation of alternative 3' splice site selection by constitutive splicing factors. RNA. 1995 May;1(3):234-45.

alternative 5' splicing

2007-12-24T00:02:00.000-08:00

The alternative donor 5' site operates in or other of two mechanisms to alter the protein product. Alternative splicing of internal exons can generate cassette, alternative 5' splice sites, alternative 3' splice sites, intron retention, and mutually exclusive splicing.

Due to alternative promoters, selection of one of several possible first exons results in variability at the 5' terminus of the mRNA. The determinative regulatory step in this mechanism is operation of a promoter rather than splice-site selection. The effect on the coding potential depends on the location of the translation initiation codon:
1. If translation initiates close to the first exons, the encoded proteins will contain alternative N termini.
2. If translation initiates in the common exon, different mRNAs will be generated that contain different 5' untranslated regions but that encode identical proteins.

Variation in alternative splicing across human tissues.
Controlling for differences in EST coverage among tissues, we found that the brain and testis had the highest levels of exon skipping. The most pronounced differences between tissues were seen for the frequencies of alternative 3' splice site and alternative 5' splice site usage, which were about 50 to 100% higher in the liver than in any other human tissue studied. Quantifying differences in splice junction usage, the brain, pancreas, liver and the peripheral nervous system had the most distinctive patterns of AS. Analysis of available microarray expression data showed that the liver had the most divergent pattern of expression of serine-arginine protein and heterogeneous ribonucleoprotein genes compared to the other human tissues studied, possibly contributing to the unusually high frequency of alternative splice site usage seen in liver. Sequence motifs enriched in alternative exons in genes expressed in the brain, testis and liver suggest specific splicing factors that may be important in AS regulation in these tissues.
Gene Yeo, Dirk Holste, Gabriel Kreiman and Christopher B Burge Free Full Text Variation in alternative splicing across human tissues. Genome Biology 2004, 5:R74

cassette exons

2007-12-22T22:05:00.000-08:00

A cassette exon is defined as an exon that is present in one mRNA transcript but absent in an isoform of the transcript.

1. Initial cassette exons are missing in one or more transcript. An initial exon is the 5' exon of a transcript. To be flagged as an initial cassette exon, the exon cannot occur as an internal exon in any transcript, that is, the initial cassette exon is the first exon in the transcript.

2. Terminal casette exons are the same as initial cassette exon, except that they occurs at the 3' end, that is, the terminal cassette exon is the final exon in the transcript.

3. Internal cassette exons are present as an internal exon in at least one transcript of the cluster, that is, neither first nor final. Internal cassette exons are presumed to be the most biologically relevant because truncated sequences may create artificial occurences of initital and terminal cassette exons.

cellular fate

2007-12-22T18:56:00.000-08:00

New eukaryotic cells arise through cellular reproduction (proliferation).

A variety of potential fates and activities await freshly arisen cells:
● differentiation into cell lines versus retained pluripotentiality
● motility and migration in response to chemotactic signals
● participation in inflammatory and immune responses
● cellular growth and metabolic activities
● cellular survival versus apoptosis
● cellular cycling and reproduction
● cellular adhesion and signaling
● malignant transformation
● pathology and disease
● metastasis
● necrosis

cellular survival

2007-12-22T18:55:00.000-08:00

To die or not to die, that is the question ...

Cellular survival is partly a matter of avoiding apoptosis, and is dependent on specific signaling cascades. Induction of programmed cell death (apoptosis) is a highly regulated process that can be suppressed by a variety of extracellular stimuli, including the various growth factors. The survival-stimulating capacity of trophic factors is attributable, at least in part, to the phosphatidylinositide 3'-OH kinase (PI3K)/c-Akt kinase cascade.

: Akt : c-akt : MEKs : MEK1 : PDK1 : phosphatidylinositide-3-OH kinase : 3-phosphoinositide-dependent protein kinase-1 : PI3K : thymoma viral proto-oncogene : v-akt :

Akt1 is 'thymoma viral proto-oncogene 1', a synonym for protein kinase B, and is a serine/threonine kinase that promotes cellular survival. Proto-oncogenes participate in a variety of normal cellular functions, but have the potential to tranform into cellular oncogenes when mutated. Proto-oncogenes normally function in the various signal transduction cascades that regulate cell growth, proliferation and differentiation. Cellular proto-oncogenes resident in transforming retroviruses are designated as c- (cellular origin) as opposed to v- (retroviral origin).

When activated, Akt exerts anti-apoptosis effects through phosphorylation of substrates that directly regulate the apoptosis machinery (Bad or caspase 9), or phosphorylation of substrates that indirectly inhibit apoptosis (human telomerase reverse transcriptase subunit (hTERT), forkhead transcription family members, or IkB kinases). Akt promotes survival in vitro when cells are exposed to different apoptotic stimuli such as growth factor deprivation, UV irradiation, matrix detachment, cell cycle discordance, DNA damage, and administration of anti-Fas antibody, TGF-β, glutamate, or bile acids.

Akt is the cellular homologue of the product of the v-akt oncogene and has 3 isoforms, Akt1, 2, and 3 (or PKB-α, -β, and -γ). Akt is activated by many growth factors, including IGF-I, EGF, βFGF, insulin, interleukin-3, interleukin-6, heregulin, and VEGF. Full activity of all three isoforms requires phosphorylation of both a site in the activation domain and another site in the C-terminal hydrophobic motif. Akt1 activation requires PDK1 phosphorylation of T308 in the activation domain and is dependent on the products of phosphatidylinositol (PI) 3-kinase (PI3-K), phosphatidylinositol 3,4 bisphosphate (PIP2) and phosphatidylinositol 3,4,5 trisphosphate (PIP3). Cellular levels of PIP2 and PIP3 are controlled by the tumor suppressor, dual-phosphatase PTEN, which dephosphorylates PIP2 and PIP3 at the 3' position.[2]

The phosphatidylinositide-3-OH kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt and the Raf/mitogen-activated protein kinase (MAPK/ERK) kinase (MEK)/mitogen-activated protein kinase (MAPK) pathways play central roles in the regulation of cell survival and proliferation. Pyruvate dehydrogenase kinase, isoenzyme 1 or 3-phosphoinositide-dependent kinase-1 (PDK1) contains an amino-terminal kinase domain and a carboxyl-terminal pleckstrin homology (PH) domain. PDK1 appears to be conserved throughout evolution (27-31). Although the PDK1 PH domain binds the lipid products of the phosphatidylinositol 3-kinase (PI3K) reaction, binding of these lipids does not alter PDK1 activity, rather it is necessary to localize PDK1 to the plasma membrane. Sphingosine, another biologically active lipid, activates PDK1 toward a variety of substrates (26). It is well established that PDK1 phosphorylates the activation loop (kinase subdomain VIII) of AGC kinase family members p70S6 kinase, Akt, protein kinase A (cAMP-dependent protein kinase), various protein kinase C (PKC) isoforms, and serum- and glucocorticoid-inducible kinases (26, 31, 33-37).(fft-s)

PDK1 promotes MAPK activation in a MEK-dependent manner, and the direct targets of PDK1 in the MAPK pathway are the upstream MAPK kinases MEK1 and MEK2. PDK1 phosphorylation sites in MEK1 and MEK2 are Ser222 and Ser[2][2][6], respectively, and are known to be essential for full activation. PDK1 is associated with maintaining the steady-state phosphorylated MEK level and cell growth. [s] MEK-1 is a dual threonine and tyrosine recognition kinase that phosphorylates and activates mitogen-activated protein kinase (MAPK). MEK-1 is in turn activated by phosphorylation.[1]

Agonist stimulation of phosphatidylinositide 3-kinase (PI 3-kinase) activates a pathway that leads to activation of ADP-ribosylation factor (ARF) 6, which regulates plasma membrane trafficking and cortical actin formation by cycling between inactive GDP and active GTP-bound conformations.

Phosphatidylinositide-3' (PI 3)-kinase participates in Kit-ligand (KL)-induced adhesion of bone marrow-derived mast cells (BMMCs) to fibronectin. The Kit receptor tyrosine kinase is a member of the PDGF receptor subfamily that mediates diverse responses including proliferation, survival, chemotaxis, migration, differentiation, and adhesion to extracellular matrix. PKCs play a dual role as both positive and negative regulators of Kit function by acting as downstream mediators in addition to participating in a negative feedback loop that down-regulates Kit receptor activity. PKC is activated by diacylgylcerol and by products of PI-3 kinase. Kit participates in the secretion of inflammatory mediators in connective tissue mast cells. Receptor-proximal PI 3-kinase activation and activation of a PKC isoform appear to have a role in Kit-mediated secretory enhancement, adhesion, and cytoskeletal reorganization.[r]

Regulation of TopBP1 oligomerization by Akt/PKB for cell survival.
Regulation of E2F1-mediated apoptosis is essential for proper cellular growth. This control requires TopBP1, a BRCT (BRCA1 carboxyl-terminal) domain-containing protein, which interacts with E2F1 but not other E2Fs and represses its proapoptotic activity. We now show that the regulation of E2F1 by TopBP1 involves the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, and is independent of pocket proteins. Akt phosphorylates TopBP1 in vitro and in vivo. Phosphorylation by Akt induces oligomerization of TopBP1 through its seventh and eighth BRCT domains. The Akt-dependent oligomerization is crucial for TopBP1 to interact with and repress E2F1. Akt phosphorylation is also required for interaction between TopBP1 and Miz1 or HPV16 E2, and repression of Miz1 transcriptional activity, suggesting a general role for TopBP1 oligomerization in the control of transcription factors. Together, this study defines a novel pathway involving PI3K-Akt-TopBP1 for specific control of E2F1 apoptosis, in parallel with cyclin-CDK-Rb for general control of E2F activities. Liu K, Paik JC, Wang B, Lin FT,
Lin WC. Regulation of TopBP1 oligomerization by Akt/PKB for cell survival. EMBO J. 2006 Sep 28; [Epub ahead of print]

Regulation of E2F1 by BRCT domain-containing protein TopBP1. [Mol Cell Biol. 2003] PMID: 12697828
TopBP1 recruits Brg1/Brm to repress E2F1-induced apoptosis, a novel pRb-independent and E2F1-specific control for cell survival. [Genes Dev. 2004] PMID: 15075294
Phosphatidylinositol 3-kinase/Akt positively regulates Fas (CD95)-mediated apoptosis in epidermal Cl41 cells. [J Immunol. 2006] PMID: 16709838
Transcriptional repression by RB-E2F and regulation of anchorage-independent survival. [Mol Cell Biol. 2001] PMID: 11313458
Specificity in the activation and control of transcription factor E2F-dependent apoptosis. [Proc Natl Acad Sci U S A. 2003] PMID: 12954980

: Akt : c-akt : PDK1 : phosphatidylinositide-3-OH kinase : 3-phosphoinositide-dependent protein kinase-1 : PI3K : thymoma viral proto-oncogene : v-akt :

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cell cycle

2007-12-22T01:48:00.000-08:00

Cellular reproduction involves the proliferation of cells by replication of genetic material, followed by:
a) Binary fission in prokaryotes and plastids derived from prokaryotes (mitochondria , chloroplasts). In binary fission, which is a form of asexual reproduction, a cell divides transversely into two daughter cells after replication.
b) Budding (yeast, spores, Hydra) is a form of asexual reproduction in which a new organism buds from a cell protuberance in a form of unequal fission.
c) Mitotic division of somatic cells in which DNA is duplicated prior to fission into cells with an equivalent chromosomal complement to that of the parent cells.
c) Meiotic division of germ cells (sexual reproduction) in which fission generates daughter cells with half the chromosomal complement of the parent cells.

Control of the Cell Cycle (animation):
Right - Cell Cycle - click to enlarge image. Phases G1 and G0, S, G2, M. Checkpoints - purple arrows at G1-S transition, during S phase, G2-M transition, anaphase of mitosis. CDKs (yellow) are modulated by association with a series of fluctuating cyclins (d, e, a, b.) The cycle is divided into non-mitotic interphase (beige) with G1 or G0, S, and G2 phases followed by mitosis (pink).

Eukaryotic cells alternate genome doubling (S-phase, synthesis) with genome splitting (mitosis, M-phase) to generate daughter cells with an identical chromosomal complement. The cell cycle consists of a signal-controlled sequence of physiological states G1 → S → G2 → M, where non-mitotic phases are termed 'interphase' (beige) and G represents 'gap'. Quiescent cells are said to be in phase G0, in which they are not participating in the cell cycle, but are metabolically active.

In a normal resting cell, intracellular signaling proteins and genes remain inactive unless activated by extracellular growth factors. When the normal resting cell is stimulated by an extracellular growth factor, signaling proteins and genes are activated and the cell proliferates.

More than one hundred genes are specifically involved in cell cycle control, these are the so called CDC-genes (cell division cycle genes). One of these genes, designated CDC28 in Saccharomyces cerevisiae or CDK1 (cyclin dependent kinase 1) in humans, controls the first step in the progression through the G1-phase of the cell cycle, and is therefore also called "start". This gene encodes a protein member of the cyclin dependent kinase family (CDKs). Half a dozen different CDK molecules have been found in humans. Cyclins are proteins formed and degraded during each cell cycle. Cyclins are so-named because their levels vary periodically during the cell cycle. Cyclins bind to the CDK molecules, thereby regulating the CDK activity and selecting the proteins to be phosphorylated. Periodic protein degradation is an important general control mechanism of the cell cycle.

Cyclins were conserved during evolution. Around ten different cyclins have been found in humans. The levels of CDK-molecules are constant during the cell cycle, but their activities vary because of the regulatory function of the cyclins. CDK and cyclin together drive the cell from one cell cycle phase to the next. Levels of cyclins D (G1), E and A (S), and B and A (mitotic) fluctuate during the cell cycle (d,e,a,b) , and binding of appropriate cyclins to the cyclin-dependent kinases (CDKs) stimulating phosphorylation and activation.

The cell cycle is a highly coordinated process that is controlled at multiple checkpoints (purple arrows) along the pathway – the G1/S and G2/M transitions of interphase as well as anaphase of mitosis. These checkpoints are critical in preserving the fidelity of the genome. Alterations in the genes that control checkpoint processes are linked to a number of human malignancies including colon, breast, lung, kidney, brain and skin cancers.

During resting conditions, Rb sequesters the E2F transcription factor within the cytosol. Phosphorylation of Rb enables dissociation of the Rb-E2F complex, which allows E2F to translocate to the nucleus, where E2F binds to the promoter region of early genes that prime the cell to progress into the S-phase of the cycle. These early genes include c-myc, cyclin A/E, and CDK1(cdc2).

Progression through the cell cycle begins (G1 → S) with the commitment to undergo cellular division, which is initiated through the activation of the cyclin D-CDK4/6 complex and the subsequent phosphorylation of the Rb-E2F complex. Activity of the cyclin D-CDK4/6 complex is regulated through binding to its respective cyclin (4/6) counterpart, phosphorylation and dephosphorylation events, and the expression of a number of CDK inhibitors (CDKI’s), which . include p15 INK4, p16 INK4, p21 Cip-1 and p27 Kip-1. Progression through G1 is further facilitated by the cyclin E-CDK2 complex.

G1 → S
Rising level of G1-cyclins (D) bind to a G1 Cdk (Cdk 4), signaling the cell to prepare the chromosomes for replication.

DNA-damage checkpoints monitor DNA damage before the cell enters S phase (G1 checkpoint),
during S phase, and after DNA replication (G2 checkpoint). Increased levels of CDK-molecules and cyclins are sometimes found in human cancers. CDK-molecules and cyclins collaborate with the products of tumor suppressor genes, such as TP53 and Rb, during the cell cycle. The p53 protein senses DNA damage and can halt progression of the cell cycle in G1. Both copies of the p53 gene must be mutated for cycle arrest to fail, so mutations in p53 are recessive and p53 qualifies as a tumor suppressor gene. The protein generated by the p53 gene acts as a signal for apoptotic cell death when DNA damage is too extensive for repair mechanisms.

S → G2
Rising level of S-phase promoting factor (SPF) — which includes cyclin A bound to Cdk2 — enter the nucleus and prepare the cell to duplicate its DNA and its centrosomes. As DNA replication continues, cyclin E is destroyed, and the level of mitotic cyclins begins to rise (in G2).

In the S-phase of the cycle, the DNA is unwound and replicated. If DNA is damaged, the fate of the cell is determined by the extent of damage. If the damage is repairable, progression through the cycle will be halted in a p53-dependent matter through p21 Cip-1, allowing sufficient time to repair the damage.

Cells monitor the presence of the Okazaki fragments on the lagging strand during DNA replication, and cells do not proceed in the cell cycle until these have disappeared.

Entry into the M-phase of the cell cycle is regulated by the cyclin B-CDK1 complex. CDK1 activity is subject to multiple levels of control in an analogous fashion to the other cyclin-dependent kinases.

G2 → M
M-phase promoting factor (a complex of mitotic cyclins with the M-phase Cdk) initiates metaphase assembly of the mitotic spindle, breakdown of the nuclear envelope, condensation of chromosomes.

Spindle checkpoints monitor any failure of spindle fibers to attach to kinetochores and arrest the cell in metaphase until all the kinetochores are attached correctly (M checkpoint), detect improper alignment of the spindle itself, block cytokinesis, and trigger apoptosis if the damage is irreparable.

M-phase promoting factor activates the anaphase-promoting complex (APC/C, cyclosome) which allows the sister chromatids assembled at the metaphase plate to separate and move to the poles during telophase, completing mitosis. The APC/C destroys cyclin B by attaching it to the protein ubiquitin, thus targetting it for destruction by proteasomes (hydrolysis by proteases). APC/C also turns on synthesis of G1 cyclin for entry into the next turn of the cycle, degrades geminin, a protein that has retained the freshly-synthesized DNA in S phase to prevent if from being re-replicated before mitosis.

This is but one mechanism by which the cell ensures that every portion of its genome is copied once — and only once — during S phase. Some cells deliberately cut the cell cycle short allowing repeated S phases without completing mitosis and/or cytokinesis (endoreplication).

In a cancer cell, mutation in a proto-oncogene that encodes an intracellular signaling protein (normally activated only by extracellular growth factors) creates an oncogene. The oncogene encodes an altered form of the signaling protein that behaves as though activated despite the absence of growth factor binding. That is, the malignant cell has escaped normal gene regulation and cell cycle control mechanisms and exhibits unchecked proliferation.

Tables Regulatory Proteins Sequences Cell signaling Cell Adhesion Molecules Second Messengers Immune Cytokines Malignant Transformation Oncogenes Proto-oncogenes

Meiosis is controlled by similar factors to those that control mitosis.

In a healthy organism, cellular proliferation of tissues is normally balanced by cell death, which occurs by programmed apoptosis. Apoptosis is induced via the stimulation of several different cell surface receptors in association with activation of caspases (cysteinyl aspartate-specific proteases). Caspases can be activated by two main pathways: the death receptor pathway and the mitochondrial pathway.

• apoptosis : checkpoints : cyclins ~ cyclin-dependent kinases & cyclin-dependent kinases : G1 : G0 : S : G2 : M : mitosis :

Tables Apoptosis vs Necrosis Apoptosis Regulatory Proteins Sequences Cell signaling Phosphate-handling enzymes Malignant Transformation Oncogenes Proto-oncogenes

DNA replication : meiosis : mitosis : mitotic spindle : replication • A • adhesion • C • CDKs . cell membranes • cellular adhesion molecules • cellular signal transduction • centrioles • chemotaxis • chloroplast • cilia & flagella • communication • concentration gradients . cyclin-dependent kinases • cytokine receptors • cytoplasm • cytoskeleton • E • energy transducers • endoplasmic reticulum • endosomes • exosome • F • flagella & cilia • G • Golgi apparatus • GPCRs • H • hormones • I • ion channels • L • lysosome • M • meiosis • microtubules • mitosis . prophase . anaphase . metaphase . telophase • mitochondrion • N • Nitric Oxide • neurotransmission • neuronal interconnections • nuclear membrane • nuclear pore • P • pinocytosis • proteasome • protein degradation • pumps • R • receptor proteins • receptor-mediated endocytosis • S • second messengers • signaling gradients • signal transduction • spindle • structure • T • transport • two-component systems • U • ubiquitin • V • vacuole • vesicle •

Human Cell Cycle . The Cell Cycle & Mitosis Tutorial . game . Mitosis: An Interactive Animation . Mitosis interactive Java tutorial .

differentiation & embryogenesis

2007-12-21T19:11:00.000-08:00

Cellular differentiation commits cells to clusters of activities specific to distinct cell lines and tissues.

In cellular reproduction, DNA replication and cell division are coordinated such that the distribution of new DNA copies to each daughter cell is ensured. Differentiation into distinct tissue types in multicellular organisms requires regulated timing of the location and expression of specific genes, such that initially totipotent (all lines - zygotes, early embryonic cells), and subsequently pluripotent (many lines – stem, meristematic) cells become committed to the characteristics of single cell lines. Differentiation involves alterations in numerous aspects of cell physiology such that structure and polarity are determined, while metabolic activity, responsiveness to signals, and gene expression are variably regulated.

epigenetic mechanisms

2007-12-20T20:17:00.000-08:00

Genetic expression has traditionally been understood as one gene-one protein, however, much genetic expression is regulated through reversible and transmissable epigenetic mechanisms, which act without an alteration of archival DNA.

Epigenetics includes the phenomenon within molecular genetics whereby a single sequence of DNA can give rise, through alternative splicing, to multiple versions of mRNA, and hence to multiple proteins, thus increasing complexity and fine-tuning genetic expression. Epigenetics also refers to DNA related mechanisms of inheritance, such as methylation and chromatin assembly.

Epigenetic regulation of gene expression is mediated through alterations in DNA methylation , covalent modifications of core nucleosomal histones, rearrangement of histones, transposon function, chromosome imprinting, type switching, telomeric silencing, and by RNA interference.

Genomic imprinting is a form of mammalian epigenetic regulation which results in the silencing of one copy (allele) of specific genes, according to parental origin. Recently, protein complexes have been discovered to manipulate nucleosomes, organize larger chromatin domains, and set boundaries of chromatin structure. Thus, key histone modifications, cis-acting elements, and regulatory proteins set, maintain, and reprogram epigenetic memory.

Epigenetic mechanisms also operate as conditional, non-programmed interactions that determine individual development [s]:
1. Interactions of cell metabolism with the external and internal physicochemical environment of an organism.
2. Interactions of tissue masses with the physical environment on the basis of physical laws inherent to condensed materials.
3. Interactions among tissues themselves.

Deregulation of epigenetic mechanisms cooperates with genetic alterations in the development and progression of malignancies. Loss of epigenetic regulation is also implicated in systemic disease. Epigenetic deregulation affects several aspects of the biology of tumor cells, including cell cycle control, differentiation, cell growth, DNA repair, and cell death.

In plants, epigenetic alterations that occur during somatic growth can be transmitted to the progeny because germ cells differentiate from somatic tissues only after many cycles of mitotic divisions.

Defining epigenetic states through chromatin and RNA - Nature Genetics: "The term 'epigenetics' is used to describe heritable changes in genome function that occur without a change in DNA sequence. As such, epigenetics lies at the heart of the cellular memory crucial for development and provides an important avenue for sustained response to environmental stimuli."

Genomics Animations and Images - Proteins & Proteomics - Animations and Images – Evolution and Phylogenetics - Animations and Images - Human Evolution - Animations and Images - Genetics of Development - Animations and Images – Cell Biology & Cancer - Animations and Images - Neurobiology - Animations and Images - Biology of Sex & Gender - Animations and Images - Genetically modified organisms - Animations and Images - Biodiversity - Animations and Images – Microbial Diversity – Animations and Images – Emerging Infectious Diseases - Animations and Images – HIV & AIDS - Animations and Images :

External : Transposons part 1, transposons part 2 : Barbara McClintock and mobile genetic elements :

ESE

2007-12-20T05:38:00.000-08:00

Exonic splicing enhancers:

Exonal sequences have a prominent role in promoting exon definition and inclusion in mature transcripts (mRNA). The best understood exonic elements include the so-called exonic splicing enhancers (ESEs). ESEs provide binding sites for SR proteins, which are thought to have a role in the initial steps of spliceosome assembly (3–5).

Sequences that act as exonic splicing silencers (ESSs) have also been described (6–11) but are less well characterized than ESEs. In some instances, ESSs have been shown to bind negative regulators belonging to the heterogeneous nuclear ribonucleoprotein (hnRNP) family (11,12).

The function of ESEs and ESSs appears to be especially important for the regulation of alternative splicing events, but these sequences probably also play a relevant role in the definition of constitutive exons.

Bipartite exonic splicing regulatory elements are known in HIV-1, papillomavirus, and the human fibronectin gene. Papillomavirus has bipartite splicing regulatory element that consists of a purine-rich positive element known as an exonic splicing enhancer (ESE) and a pyrimidine-rich negative element known as an exonic splicing suppressor (ESS). [s]

ESS

2007-12-20T05:05:00.000-08:00

Exonic splicing silencers.
Exonal sequences have a prominent role in promoting exon definition and inclusion in mature transcripts (mRNA). Sequences that act as exonic splicing silencers (ESSs) have been described (6–11) but are less well characterized than ESEs. In some instances, ESSs have been shown to bind negative regulators belonging to the heterogeneous nuclear ribonucleoprotein (hnRNP) family (11,12).

The best understood exonic elements include the so-called exonic splicing enhancers (ESEs). ESEs provide binding sites for serine rich, SR proteins, which are thought to have a role in the initial steps of spliceosome assembly (3–5).

ESEs and the ESSs are capable of regulating splicing of heterologous pre-mRNAs containing suboptimal splice sites. The function of ESEs and ESSs appears to be especially important for the regulation of alternative splicing events, but these sequences probably also play a relevant role in the definition of constitutive exons.

exon skipping

2007-12-20T01:09:00.000-08:00

Exon skipping is the most frequent alternative splicing mechanism known in mammals, and as such is a major contributor to protein diversity in mammals. Exon skipping results in the loss of an exon in the alternatively spliced mRNA.

Alternative splicing can alter the mRNA product in several ways. At the simplest level, an exon can be removed (exon skip), lengthened or shortened (alternative 5' or 3' splicing). In addition, introns may be retained in a lengthened mRNA.

Many disease-associated mutations also affect pre-mRNA splicing, usually causing inappropriate exon skipping. SR proteins are essential splicing factors that recognize exonic splicing enhancers and drive exon inclusion. Alternative splicing is reported to regulate the sub-cellular localization of divalent metal transporter 1 isoforms and the NMDA R1 receptor gene.

Conserved sequence elements associated with exon skipping.
One of the major forms of alternative splicing, which generates multiple mRNA isoforms differing in the precise combinations of their exon sequences, is exon skipping. While in constitutive splicing all exons are included, in the skipped pattern(s) one or more exons are skipped. The regulation of this process is still not well understood; so far, cis- regulatory elements (such as exonic splicing enhancers) were identified in individual cases. We therefore set to investigate the possibility that exon skipping is controlled by sequences in the adjacent introns. We employed a computer analysis on 54 sequences documented as undergoing exon skipping, and identified two motifs both in the upstream and downstream introns of the skipped exons. One motif is highly enriched in pyrimidines (mostly C residues), and the other motif is highly enriched in purines (mostly G residues). The two motifs differ from the known cis-elements present at the 5' and 3' splice site. Interestingly, the two motifs are complementary, and their relative positional order is conserved in the flanking introns. These suggest that base pairing interactions can underlie a mechanism that involves secondary structure to regulate exon skipping. Remarkably, the two motifs are conserved in mouse orthologous genes that undergo exon skipping.
Miriami E, Margalit H, Sperling R. Conserved sequence elements associated with exon skipping. Nucleic Acids Res. 2003 Apr 1;31(7):1974-83. Free Full Text Article

gene regulation and biological evolution

2007-12-18T19:06:00.000-08:00

Gene regulation, rather than genetic mutation plays an important role in some rapid adaptive speciations.

Most of the 50 or so species of freshwater stickleback fish are descendents of marine stickleback that colonized lakes and streams at the end of the last ice age about 10,000 years ago. Researchers have discovered that rapid speciation displaying different levels of armor plating in sticklebacks results not from gene mutations, but rather from different regulation of a single gene, the Eda gene that codes for the protein ectodermal dysplasin. "Evolution of the fish is based on how the Eda gene is used; how, when and where it is activated during embryonic growth." HHMI News Researchers Trace Evolution to Relatively Simple Genetic Changes.

Widespread parallel evolution in sticklebacks by repeated fixation of Ectodysplasin alleles.
Major phenotypic changes evolve in parallel in nature by molecular mechanisms that are largely unknown. Here, we use positional cloning methods to identify the major chromosome locus controlling armor plate patterning in wild threespine sticklebacks. Mapping, sequencing, and transgenic studies show that the Ectodysplasin (EDA) signaling pathway plays a key role in evolutionary change in natural populations and that parallel evolution of stickleback low-plated phenotypes at most freshwater locations around the world has occurred by repeated selection of Eda alleles derived from an ancestral low-plated haplotype that first appeared more than two million years ago. Members of this clade of low-plated alleles are present at low frequencies in marine fish, which suggests that standing genetic variation can provide a molecular basis for rapid, parallel evolution of dramatic phenotypic change in nature.
Colosimo PF, Hosemann KE, Balabhadra S, Villarreal G Jr, Dickson M, Grimwood J, Schmutz J,
Myers RM, Schluter D, Kingsley DM. Widespread parallel evolution in sticklebacks by repeated fixation of Ectodysplasin alleles. Science. 2005 Mar 25;307(5717):1928-33.
Comment in: Science. 2005 Mar 25;307(5717):1890-1..

How many genetic changes control the evolution of new traits in natural populations? Are the same genetic changes seen in cases of parallel evolution? Despite long-standing interest in these questions, they have been difficult to address, particularly in vertebrates. We have analyzed the genetic basis of natural variation in three different aspects of the skeletal armor of threespine sticklebacks (Gasterosteus aculeatus): the pattern, number, and size of the bony lateral plates. A few chromosomal regions can account for variation in all three aspects of the lateral plates, with one major locus contributing to most of the variation in lateral plate pattern and number. Genetic mapping and allelic complementation experiments show that the same major locus is responsible for the parallel evolution of armor plate reduction in two widely separated populations. These results suggest that a small number of genetic changes can produce major skeletal alterations in natural populations and that the same major locus is used repeatedly when similar traits evolve in different locations.
The Genetic Architecture of Parallel Armor Plate Reduction in Threespine Sticklebacks. (Free Full Text Research Article) PLos Biology Volume 2 Issue 5 MAY 2004.

Evolution. The synthesis and evolution of a supermodel. [Science. 2005] PMID: 15790836
The genetic architecture of parallel armor plate reduction in threespine sticklebacks. [PLoS Biol. 2004] PMID: 15069472
Parallel genetic basis for repeated evolution of armor loss in Alaskan threespine stickleback populations. [Proc Natl Acad Sci U S A. 2004] PMID: 15069186
The master sex-determination locus in threespine sticklebacks is on a nascent Y chromosome. [Curr Biol. 2004] PMID: 15324658
Lateral plate evolution in the threespine stickleback: getting nowhere fast. [Genetica. 2001] PMID: 11838781

More HHMI articles: Genetic Control of Vertebrate Skeletal Development. Also Evolution's Mirror in a Fish's Spines (04.14.04) and Fish May Show How Nature Diversifies(12.19.01) and more HHMI Genes We Share: Focusing on Skeletons and New Gene Knockouts Reveal "Master Planners" of the Skeleton(07.17.03)

More from PubMed

Evolutionary origin of the medaka Y chromosome. [Curr Biol. 2004] PMID: 15380069
Cloning of the dmrt1 gene of Xiphophorus maculatus: dmY/dmrt1Y is not the master sex-determining gene in the platyfish. [Gene. 2003] PMID: 14604792
Construction and initial analysis of bacterial artificial chromosome (BAC) contigs from the sex-determining region of the platyfish Xiphophorus maculatus. [Gene. 2002] PMID: 12354660
Genetic mapping of Y-chromosomal DNA markers in Pacific salmon. [Genetica. 2001] PMID: 11841186
Sex determination and sex chromosome evolution in the medaka, Oryzias latipes, and the platyfish, Xiphophorus maculatus. [Cytogenet Genome Res. 2002] PMID: 12900561
...

Natural selection and parallel speciation in sympatric sticklebacks. [Science. 2000] PMID: 10634785
Reproductive character displacement of male stickleback mate preference: reinforcement or direct selection? [Evolution Int J Org Evolution. 2004] PMID: 15212390
Parallel evolution of sexual isolation in sticklebacks. [Evolution Int J Org Evolution. 2005] PMID: 15807421
Testing alternative models for sexual isolation in natural populations of Littorina saxatilis: indirect support for by-product ecological speciation? [J Evol Biol. 2004] PMID: 15009262
Divergent selection and the evolution of signal traits and mating preferences. [PLoS Biol. 2005] PMID: 16231971
..

Evolutionary biology: lost and found. [Nature. 2004] PMID: 15085113
Reduce your pelvis in 10000 years or less. [Dev Cell. 2004] PMID: 15130486
The master sex-determination locus in threespine sticklebacks is on a nascent Y chromosome. [Curr Biol. 2004] PMID: 15324658
The genetic architecture of parallel armor plate reduction in threespine sticklebacks. [PLoS Biol. 2004] PMID: 15069472
Fishing for the secrets of vertebrate evolution in threespine sticklebacks. [Dev Dyn. 2005] PMID: 16252286
..

Fishing for the secrets of vertebrate evolution in threespine sticklebacks. [Dev Dyn. 2005] PMID: 16252286
Parallel genetic basis for repeated evolution of armor loss in Alaskan threespine stickleback populations. [Proc Natl Acad Sci U S A. 2004] PMID: 15069186
Widespread parallel evolution in sticklebacks by repeated fixation of Ectodysplasin alleles. [Science. 2005] PMID: 15790847
Genetic and developmental basis of evolutionary pelvic reduction in threespine sticklebacks. [Nature. 2004] PMID: 15085123
The master sex-determination locus in threespine sticklebacks is on a nascent Y chromosome. [Curr Biol. 2004] PMID: 15324658
..

The master sex-determination locus in threespine sticklebacks is on a nascent Y chromosome. [Curr Biol. 2004] PMID: 15324658
Fishing for the secrets of vertebrate evolution in threespine sticklebacks. [Dev Dyn. 2005] PMID: 16252286
How much of the variation in adaptive divergence can be explained by gene flow? An evaluation using lake-stream stickleback pairs. [Evolution Int J Org Evolution. 2004] PMID: 15562693
Adaptive divergence and the balance between selection and gene flow: lake and stream stickleback in the Misty system. [Evolution Int J Org Evolution. 2002] PMID: 12144020
Speciation in reverse: morphological and genetic evidence of the collapse of a three-spined stickleback (Gasterosteus aculeatus) species pair. [Mol Ecol. 2006] PMID: 16448405
...

genetic variation

2007-12-18T19:03:00.000-08:00

Genetic mutations involve structural, usually transmissible change in DNA or RNA within a cell or organism. Somatic mutations affect the cells of an organism, yet are not trasmitted to the next generation unless they affect the germline, those zygotes, such as ova and sperm that are committed to reproduction. Transmissible mutations affect the germline or result from errors during replication and cell division during reproduction.

Sequence mutations result from nucleotide substitutions, insertions, deletions, or re-arrangements of gene segments. On a larger scale, chromosomes are altered during replication and cell division by deletion, duplication, inversion, recombination, translocation, transposition, and non-disjunction.

Depending upon their effects upon an organism within a particular environment, mutations may be neutral, beneficial, or deleterious. The commonest mutations affect single nucleotides (point mutations or SNPs). Because the genetic code is redundant, many single nucleotide substitutions are neutral.

The genetic makeup of descendent diploid populations differs from that of the parental population by virtue of recombination, the random shuffling of genes during meiosis.

Insertion of mobile genetic elements, transposons and retrotransposons, increases genetic variability. The human genome, for example, includes approximately 500,000 Alu elements located within introns, and 25,000 of those could become new exons, coding for polypeptide sequences, by undergoing a single-point mutation.

As a result of alternative splicing, mutations that alter a splice site or a nearby regulatory sequence can have subtle effects by shifting the ratio of the resulting proteins without entirely eliminating any form. Alternative splicing also generates new polypeptide combinations from already existing code. Recently, researchers have demonstrated that modification of regulation of a single gene has enabled rapid phenotypic speciation in sticklebacks.

Alternative promoters enable mammals to extract more variability from fixed DNA sequences by regulating location and timing of transcription, adjusting the timing of protein production or generating alternative proteins by modifying the location at which transcription commences. Roughly 40-50 % of human and mouse genes have alternative promoters, which are more active during embryological development, and which display evolutionary conservation.

Statistical, population mechanisms operate upon allele frequencies within populations. Natural selection involves transmission of gene combinations that derived from parental genotypes that have proven favorable to survival and to reproductive success. Purely random bottleneck and randomly isolated founder effects are mechanisms of genetic drift, the random transmission of alleles between generations. Gene flow refers to the movement of genes from the gene pool of one population into that of another, brought about by movement of individual animals, gametes, or spores. Gene flow increases biodiversity and acts against speciation pressures by rendering two populations more similar to each other.

homeobox genes

2007-12-17T09:11:00.000-08:00

Homeobox genes, part of the homeobox family, contain the homeobox DNA sequence that is involved in morphogenesis.

Homeobox genes encode transcription factors, which are proteins that bind to DNA at specific promoter or enhancer or response element sequences or sites, at which they regulate transcription. As such, transcription factors are required for the recognition of specific stimulatory sequences in eukaryotic genes by RNA polymerases. Transcription factors can be selectively activated or deactivated by other proteins, often as the final step in signal transduction.

Homeobox genes were first identified in Drosophila melanogaster, and have subsequently been discovered in species from sponges to vertebrates.

Hox genes are a highly conserved subgroup of homeobox genes that are found in the Hox cluster (homeodomain, Hox complex). Hox genes function in determining the longitudinal axis of the body plan (bauplan). As regulatory genes they establish the identity of particular body regions, so Hox genes determine the location of body segments in a developing fetus or larva.

Homeotic genes in plants (MADS-box genes) are not homologous to Hox genes in animals. Since plants and animals do not share the same homeotic genes, it seems likely that homeotic genes were evolved once in the early evolution of animals and once separately in the early evolution of plants.

Mutations in homeobox genes alter gene regulation, and hence cause phenotypic changes.

Gtx is a homeodomain transcription factor. Gtx mRNA accumulates in parallel with the RNAs encoding the major structural proteins of myelin, myelin basic protein (MBP), and proteolipid protein (PLP) during postnatal brain development. Gtx is a sequence-specific DNA-binding protein, which binds DNA sequences containing a core AT-rich homeodomain binding site. [s]

homeodomain

2007-12-17T09:10:00.000-08:00

Many genes in homeotic gene clusters contain a common sequence. The recurring motif is to be a sequence called the homeobox. The homeobox encodes a 60 residue protein homeodomain, which has a high content of basic residues. Proteins containing the homeodomain are localized in the nucleus and bind to specific DNA sequences. The homeodomain contains the helix-turn-helix motif, which is present in prokaryotic DNA-binding proteins such as Cro and lambda repressor.

[] 3D image of transcription factor homeodomain - helix-turn-helix [] image gene regulating protein 3Cro [] image DNA binding protein Homeodomain protein segment bound to DNA []

The plant homeodomain (PHD) zinc finger domain has a C4HC3-type motif, and is widely distributed in eukaryotes, being found in many chromatin regulatory factors [3].[s]

Homeotic : Homeotic genes affect embryo development by specifying the character of a body segment. Homeotic mutations produce morphologic changes in body shape (bauplan) and can be an effective means for evolutionary change because affected organisms remain reproductively viable. Homeotic mutations cause one member of a repetitive series to assume the identity of another member, for example, the transformation of sepals into petals.

[] 3D image of transcription factor homeodomain - helix-turn-helix [] image gene regulating protein 3Cro [] image DNA binding protein Homeodomain protein segment bound to DNA []

₪ cell cycle ₪ differentiation & embryogenesis ₪ homeobox genes ₪ homeodomain ₪ molecular switches ₪ regulation ₪ cell signaling ₪ Wnt signaling ~ transcription factors ~
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intron retention

2007-12-16T10:04:00.000-08:00

Intron retention is defined by the presence of a transcript-confirmed intron within a transcript-confirmed exon. Intron retention occurs when introns are not spliced out of the RNA transcript, resulting in the intron(s) being retained within the mRNA as part of an exon. This lengthening mechanism the commonest form of alternative splicing in plants and lower multicellular organisms.

Intron retention is probably the earliest version of alternative splicing to have evolved. The splicing machinery of single-celled organisms, such as yeast, operates by recognizing introns, in contrast with the SR protein system of higher organisms, which defines exons for the basal machinery.

In unicellular organisms, the splicing machinery can recognize only short (less than 500 nt) to recognition of short exons in long intron segments.

The average human protein-coding gene, for example, is 28,000 nucleotides long, and has 8.8 exons separated by 7.8 introns. Human exons are relatively short, typically about 120 nucleotides, whereas the introns can range from 100 to 100,000 nucleotides in length. Humans have the highest number of introns per gene of any organism and much of the energy we consume is devoted to the DNA repair and maintenance of introns, transcription, pre-mRNA splicing (removal of introns), and breakdown of introns at the end of the splicing reaction. In addition to energy costs, breakdown of splicing regulation results in disease.

The advantage of alternative splicing expresses itself as the roughly 90,000 human proteins coded by a mere 25,000 genes. Yet a mouse possesses almost the same number of genes as a human. Although approximately 100 million years have passed since mice and men shared a common ancestor, 99 percent of both human and mouse genes derive from that ancestor. Most of these genes share the same intron and exon arrangement, and the nucleotide sequences within our exons are also conserved to a high degree. However, roughly one quarter of the alternatively spliced exons in both genomes are specific either to human or to mouse. Thus, these alternately spliced exons have the potential to create species-specific proteins that could be responsible for diversification between the species. In fact, one category of alternatively spliced exons is unique to primates (humans, apes and monkeys) and probably contributed to primates' divergence from other mammals.

These primate-specific exons derive from mobile genetic elements called Alu elements that belong to a larger class of elements known as retrotransposons, which are short sequences of DNA able to replicate themselves and then to reinsert those copies back into the genome at random positions. Retrotransposons are found in almost all genomes, and they have had a profound influence by contributing to the genomic expansion that accompanied the evolution of multicellular organisms. Almost half of the human genome is made up of transposable elements, Alus being the most abundant.

ISE

2007-12-16T05:38:00.000-08:00

Intronic splicing enhancer:

A novel intronic cis element, ISE/ISS-3, regulates rat fibroblast growth factor receptor 2 splicing through activation of an upstream exon and repression of a downstream exon containing a noncanonical branch point sequence.
"The selection of a cassette exon for splicing is further determined by RNA cis elements generally referred to as exonic or intronic splicing enhancers (ESEs or ISEs) and exonic or intronic splicing silencers (ESSs or ISSs). For the most part, it appears that these cis elements function by binding to splicing regulatory proteins that stimulate or inhibit exon definition. Most alternatively spliced cassette exons contain more than one such regulatory cis element in the exon and/or in the flanking introns, and as such, combinatorial models of splicing regulation have been proposed whereby inclusion or skipping of an exon is determined by the net activity of several proteins associated with these elements (7, 46). Studies of numerous alternatively spliced transcripts support such models of combinatorial control (7, 46).

A particularly robust example of regulation by a mammalian tissue-specific splicing factor is that seen with the neural-specific Nova proteins, Nova-1 and Nova-2, that are expressed exclusively in distinct subsets of neurons and that may be sufficient to achieve brain-specific alternative splicing of several transcripts (52). It is likely that the splicing outcome for many alternatively spliced mammalian transcripts results from the combinatorial effects of cell-type-specific factors as well as differential expression of other regulatory factors." Hovhannisyan RH,
Carstens RP. A Novel Intronic cis Element, ISE/ISS-3, Regulates Rat Fibroblast Growth Factor Receptor 2 Splicing through Activation of an Upstream Exon and Repression of a Downstream Exon Containing a Noncanonical Branch Point Sequence. (Free Full Text Article) Molecular and Cellular Biology, January 2005, p. 250-263, Vol. 25, No. 1

A Non-sequence-specific double-stranded RNA structural element regulates splicing of two mutually exclusive exons of fibroblast growth factor receptor 2 (FGFR2). [J Biol Chem. 2002] PMID: 12393912
An intronic splicing silencer causes skipping of the IIIb exon of fibroblast growth factor receptor 2 through involvement of polypyrimidine tract binding protein. [Mol Cell Biol. 2000] PMID: 10982855
A stem structure in fibroblast growth factor receptor 2 transcripts mediates cell-type-specific splicing by approximating intronic control elements. [Mol Cell Biol. 2003] PMID: 14645542
Characterization of sequences and mechanisms through which ISE/ISS-3 regulates FGFR2 splicing. [Nucleic Acids Res. 2006] PMID: 16410617
Characterization of the intronic splicing silencers flanking FGFR2 exon IIIb. [J Biol Chem. 2005] PMID: 15684416

ISS

2007-12-16T05:05:00.000-08:00

Intronic splicing suppressor:

modified: Pre-mRNA splicing is a sophisticated and ubiquitous nuclear process, which is a natural source of cancer-causing errors in gene expression. Intronic splice-site mutations of tumor suppressor genes often cause exon-skipping events that truncate proteins just like classical nonsense mutations. Also, many studies over the last 20 years have reported cancer-specific alternative splicing in the absence of genomic mutations. Affected proteins include transcription factors, cell signal transducers, and components of the extracellular matrix.
Venables JP. Aberrant and alternative splicing in cancer. (Free Full Text Article) Cancer Res. 2004 Nov 1;64(21):7647-54.

Aberrant splicing in several human tumors in the tumor suppressor genes neurofibromatosis type 1, neurofibromatosis type 2, and tuberous sclerosis 2. [Cancer Res. 2002] PMID: 11888927
Splice variants as cancer biomarkers. [Clin Biochem. 2004] PMID: 15234240
Disruption of WT1 gene expression and exon 5 splicing following cytotoxic drug treatment: antisense down-regulation of exon 5 alters target gene expression and inhibits cell survival. [Mol Cancer Ther. 2004] PMID: 15542786
A polar mechanism coordinates different regions of alternative splicing within a single gene. [Mol Cell. 2005] PMID: 16061185
Alterations of pre-mRNA splicing in cancer. [Genes Chromosomes Cancer. 2005] PMID: 15648050

Free Full Text Articles:
Functional studies on the ATM intronic splicing processing element. [Nucleic Acids Res. 2005]
Solution structure of the pseudo-5' splice site of a retroviral splicing suppressor. [RNA (2004), 10:1388-1398. ]

micro RNA

2007-12-12T15:06:00.000-08:00

MicroRNAs are a large class of 21 to 24 nucleotide non-coding RNAs that have probable epigenetic regulatory roles in animals and plants.

MicroRNAs Have Shaped The Evolution Of The Majority Of Mammalian Genes : modified: "In a paper published last January in the journal Cell, Bartel's lab, in collaboration with Chris Burge's lab at MIT, presented evidence that one third of human genes are regulated by microRNAs. In this new study, published online Nov. 24 in Science, the researchers demonstrate that microRNAs affect the expression or evolution of the majority of human genes.

Nearly all genes, the authors explain, contain short sequences that match portions of microRNAs. Some of these potential microRNA target sites are evolutionarily "conserved," meaning that they show up in the same spot on the same gene across species as disparate as the mouse and the chicken. The authors of last January's Cell paper showed that thousands of human genes contain microRNA sites that are conserved in this way. To the extent that evolution has preserved these sites more than would be expected by chance, scientists have regarded them as sites that microRNAs target.

In the new study, scientists in the Bartel lab designed an experiment that zeroed in on these nonconserved targets. Grimson took mRNAs whose target sequences were not conserved and exposed them to microRNAs, which latched on without a problem. The experiment proved that a matching sequence is generally sufficient to disrupt mRNA's ability to make protein.

Kyle Kai-How Farh, a graduate student in Bartel's lab, found that mRNAs with nonconserved sites were generally absent in cells with corresponding microRNAs--more absent than statistical models suggested. The researchers concluded that over the course of evolution many mRNAs, in order to maintain their functions and ensure fitness of the organism, have quickly lost sites that pair up with microRNAs.

In addition to the thousands of cases where genes have avoided microRNA targeting, Farh also investigated the opposite extreme, cases where genes have maintained microRNA target sites over the course of evolution. He found that as immature muscle cells stop dividing and become mature muscle cells, microRNAs are activated and suppress genes that are no longer needed at such high levels in the mature muscle. "Many of these evolutionarily conserved microRNA targets are known to be active in the processes of cell proliferation, development, and cancer," says Farh. "Our genomes have good reason to maintain the microRNA targeting sites necessary for turning down these genes at the appropriate place and time."An emerging idea is that microRNAs often act to reduce the quantity of protein a gene produces without shutting it off all together. "We think the microRNAs are sometimes having what you can call a dampening effect," says Bartel, who is also a Howard Hughes Medical Institute investigator and MIT professor of biology. "They appear to be helping cells achieve optimal levels of proteins.""

molecular switches

2007-12-12T09:05:00.000-08:00

Long before nanotechnology, biochemical molecular switches evolved to function within signal transduction pathways that control cellular differentiation, the cell cycle and cellular proliferation.

: cAMP-dependent protein kinase : MAP kinases : PKA : PKCs : protein kinase A : protein kinase Cs : Ras : receptor tyrosine kinases : serine/threonine kinases : Tissues :

As central components of cell signaling networks, receptor tyrosine kinases (RTKs) play crucial roles in physiological processes, such as embryogenesis, differentiation, neurite outgrowth, cell proliferation, anti-apoptotic signaling and death of cells (apoptosis).

The serine/threonine kinases comprise a large family, which serve in in signal transduction pathways for receptors of the TGF-β ligand superfamily.

Protein kinase A, or cAMP-dependent protein kinase is an enzymes whose catalytic (protein phosporylating) activity is modulated by cAMP levels. PKA is highly conserved with RTKs.

Protein kinase Cs, are enzymes that exhibit specific patterns of tissue expression and activation and are maximally active in the presence of calcium ion and diacylglycerol. PKC activity is mediated by receptors that are coupled to activation of phospholipase C-gamma (PLC-gamma), which contains SH2 domains that enable it to interact with tyrosine phosphorylated RTKs. Phospholipases D and A2 (PLD, PLA2) sustain the activation of PKC through their hydrolysis of membrane phosphatidylcholine (PC). Activation of PLC-gamma results in hydrolysis of membrane phosphatidylinositol bisphosphate (PIP2), which leads to an elevation of intracellular diacylglycerol (DAG) and inositol trisphosphate (IP3), which interacts with intracellular membrane receptors to effect release of stored calcium ions. PKCs are involved in signal transduction pathways initiated by specific hormones, growth factors and neurotransmitters.

Mitogen activated protein kinases (MAP kinases), act as switch kinases that transmits information of increased intracellular tyrosine phosphorylation to that of serine/threonine phosphorylation. MAP kinases are also called ERKs for extracellular-signal regulated kinases, microtubule associated protein-2 kinase (MAP-2 kinase), myelin basic protein kinase (MBP kinase), ribosomal S6 protein kinase (RSK-kinase) and EGF receptor threonine kinase (ERT kinase). Maximal MAP kinase activity requires phosphorylation of both tyrosine and threonine residues.

Ras genes encode proteins of the Ras superfamily, which includes Rab, Ras, and Rho (including Rho-GTPase) families. Proteins of the Ras superfamily are important molecular switches in signal transduction pathways. Ras proteins are involved in cell adhesion, apoptosis, cell migration, cytoskeletal integrity, cell proliferation, and, when unregulated, neoplasia.

Tissues / Functions:

Cytoskeleton:
The phagosome cAMP/PKA system behaves as a molecular switch that regulates phagosome actin and maturation in macrophages.[pm]

Neural tissue:
Synapsins are synaptic vesicle-associated phosphoproteins involved in the regulation of neurotransmitter release and synapse formation; they are substrates for multiple protein kinases that phosphorylate them on distinct sites. Phosphorylation of synapsin domain A is essential for the synapsin-induced enhancement of neurotransmitter release, suggesting that endogenous kinases phosphorylating the synapsin domain play a central role in the regulation of the efficiency of the exocytotic machinery.[s & fft-s] Cyclic AMP (cAMP) promotes neurite outgrowth in a variety of neuronal cell lines through the activation of protein kinase A (PKA). The nerve growth-promoting action of cAMP/PKA is mediated in part by the phosphorylation of synapsins at a single amino acid residue.[r] :

Neuregulin gene switch for myelin production.

Renal:
Mutations in the gene encoding the kinase WNK4 cause pseudohypoaldosteronism type II (PHAII), a syndrome featuring hypertension and hyperkalemia. Wnk4 is a molecular switch that regulates the balance between NaCl reabsorption and K(+) secretion by altering the mass and function of the DCT through its effect on NCC.[p]

Tumorigenesis:
Ras genes encode proteins of the Ras superfamily, which are important molecular switches in signal transduction pathways. Ras proteins are involved in cell adhesion, apoptosis, cell migration, cytoskeletal integrity, cell proliferation, and, when unregulated, neoplasia.The superfamily includes Ras, Rho, and Rab families. The Rho family includes Rho-GTPase.

The Ras GTPases act as binary switches for signal transduction pathways that are important for growth regulation and tumorigenesis. Despite the biochemical simplicity of this switch, Ras proteins control multiple pathways, and the functions of the four mammalian Ras proteins are not overlapping. One recently emerging model suggests that a single Ras protein can control different functions by acting in distinct cellular compartments. The fission yeast Schizosaccharomyces pombe expresses only one Ras protein that controls two separate evolutionarily conserved pathways. Whereas Ras localized to the plasma membrane selectively regulates a MAP kinase pathway to mediate mating pheromone signaling, Ras localized to the endomembrane activates a Cdc42 pathway to mediate cell polarity and protein trafficking -providing unambiguous evidence for compartmentalized signaling of Ras.

regulation

2007-12-07T19:26:00.000-08:00

Regulation is key to cellular differentiation, to control of gene expression, and to control of cellular metabolic processes. Gene regulation is key to biological evolution because alterations in regulatory genes can amplify small alterations in genotype into large alterations of phenotype.

Tables Regulatory Proteins Sequences gene regulation in E.coli :

1. Cellular differentiation – within the cell cycle, DNA replication and cell division are coordinated such that the distribution of new DNA copies to each daughter cell is ensured. Cell cycle entry and progression is regulated by checkpoints and by a series of CDC gene encoded cyclin-CDKs. Differentiation into distinct tissue types in multicellular organisms requires regulated timing of the location and expression of specific genes, such that initially totipotent (all lines - zygotes, early embryonic cells), and subsequently pluripotent (many lines – stem, meristematic) cells become committed to the characteristics of single cell lines. Differentiation involves alterations in numerous aspects of cell physiology such that structure and polarity are determined, while metabolic activity, responsiveness to signals, and gene expression are variably regulated.

2. Regulation of gene expression :
Prokaryotes:
(a) long-term regulation of metabolism in bacteria is achieved through the control of initiation of transcription by such mechanisms as sigma factors, repressor proteins during induction and repression, and by the attenuation of many biosynthetic operons.

Control of prokaryotic gene expression is brought about by control of the rate of transcriptional initiation by two DNA promoter sequence elements that promote recognition of transcriptional start sites by RNA polymerase. Regulatory accessory proteins alter the activity of RNA polymerase at a given promoter by affecting the ability of RNA polymerase to recognize start-sites. These regulatory proteins can act both positively (activators) and negatively (repressors). Proteins with sequences termed operators regulate the accessibility of promoter regions to prokaryotic DNA. The operator region is adjacent to the promoter elements in most operons, and in most cases the sequences of the operator bind a repressor protein. However, E. coli possesses several operons that contain overlapping sequence elements, one that binds a repressor and one that binds an activator.

Two major modes of transcriptional regulation in bacteria (E. coli) utilize repressor proteins to control the expression of operons.
1. Catabolite-regulated operons employ repressor proteins to down-regulate operons that produce gene products necessary for the utilization of energy. A classic example of a catabolite-regulated operon is the lac operon, responsible for obtaining energy from b-galactosides such as lactose.
2. Attenuated operons regulate operons that produce gene products necessary for the synthesis of small biomolecules such as amino acids. Expression of the an attenuated operon class of operons is repressed by sequences within the transcribed RNA. A classic example of an attenuated operon is the trp operon, responsible for the biosynthesis of tryptophan. Table gene regulation in E.coli .

In eukaryotes, mechanisms for control of gene expression are more varied than in prokaryotes
(a) Most commonly affect the rate of transcription is regulated,
(b) Some mechanisms alter the rate of RNA processing within the nucleus.
(c) Alternative promoters can modify the location at which transcription commences, altering the protein transcribed from a particular DNA sequence.
(c) Some control mechanisms affect the stability and degradation of RNA molecules (nonsense-mediated decay, nonstop decay).
(d) Some regulatory mechanisms control the efficiency of ribosomal translation into ribosomal polypeptides and proteins.
(e) Much variability in the proteome is provided by alternative splicing, which generates different proteins from the same genome.
(f) Epigenetic mechanisms modify mRNAs.

Table Regulatory Proteins Sequences Comparisons of Eubacteria, Archaea, and Eukaryotes Gene Regulation in E.coli .

3. Regulation of metabolism primarily involves modulation of key steps that determine the flux of metabolites through various pathways. Metabolism is regulated such that (a) cell components are maintained at the proper concentrations, despite alterations in the environmental milieu, and such that (b) energy and materials are conserved.

Localization of enzymes and metabolites in separate compartments of a cell assists in regulation and coordination of metabolic activity. The activity of a metabolic pathway is often controlled by the end-products of the pathway (a)through feedback inhibition of regulatory enzymes located at the start of the sequence, or (b) at branch points.

Enzymes control the flux of metabolites through metabolic pathways, regulating the rates of metabolic pathways, and mechanisms exist to control the activity or synthesis of allosteric and inducible/repressible enzymes. The activity of regulatory enzymes can be altered through reversible binding of effectors to a regulatory (allosteric) site that is separate from the catalytic site, or through covalent modification of the enzyme. Regulation of enzyme activity operates rapidly and serves as a fine-tuning mechanism to adjust metabolism from moment to moment.

Glycolysis in bacteria Comparison of Photosynthesis and Respiration Enzymes Function Krebs Cycle Enzymes Cofactors of Krebs Cycle Second Messengers Phosphate-handling Enzymes Electron Transport Chain vs Oxidative Phosphorylation Regulatory Proteins Sequences Gene Regulation in E.coli Cell signaling Second Messengers .

· adenylyl (adenylate) cyclase · calcium ions · cAMP-dependent protein kinase · CDKs · cyclin-dependent kinases · DAG · diacylglycerol · DNA ligases · ERKs· GPCRs · GPCR families · guanylate cyclases · guanyl cyclase · inositol triphosphate · IP3 · MAP kinases · mitogen activated protein kinases · phosphatases · phosphodiesterases · phospolipases · phosphorylation · PKA · PKC · phospholipase C-gamma · protein kinase A · protein kinase C · protein tyrosine kinases (PTKs) · receptor tyrosine kinases · second messengers · second messenger cAMP · second messenger cGMP · signal transduction · two-component systems ·

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cell signaling

2007-12-06T15:26:00.000-08:00

Cells, whether unicellular organisms or cells within multicellular organisms, respond to signals within their environment. Such signals include mechanical stimuli (light, sound) and chemicals. The origin of chemical stimuli (ligands) may be the cell itself (autocrine), adjacent cells (paracrine), the plasma membrane of adjacent cells (contact inhibition), or distant cells (endocrine).

Received signals are transduced into cellular effects by a variety of signal → receptor → enzyme → cellular impact pathways. Extracellular signals impinge upon specialized membranous receptors. Sensory transduction involves the conversion of mechanical or chemical stimuli to cellular signals or neurophysiological signals. Intracellular signals enable communication within cells, while intercellular signals enable communication between cells.

Neurotransmission incorporates interaction between neurotransmitters and specific receptor proteins. Cytokines mediate paracrine stimulation, and hormones mediate endocrine stimulation.

Cellular responses to signalling molecules include alterations in gene expression (transcription), alteration of electrophysiological charge, and alteration of metabolic activity of the cell. Since signaling processes regulate fundamental cellular responses, disturbance of these processes can lead to the development of various human diseases involving disruptions of immunity, abnormal proliferation (cancers), or metabolic disturbance (endocrine disorders).

Wnt signaling

2007-12-03T10:04:00.000-08:00

The Wnt signaling pathway controls cell proliferation and body patterning throughout development.

Several cytoplasmic Wnt regulators (β-catenin, Bcl-9/Lgs, APC, Axin) also appear transiently in the nucleus. At intercellular adherens junctions, β-catenin is an integral component of E-cadherin complexes. β-Catenin also recruits chromatin remodeling complexes, promoting transcription in the nucleus. The APC tumor suppressor is a component of the cytoplasmic β- catenin destruction complex, but counteracts β-catenin transactivation and histone H3K4 methylation at Wnt target genes. APC also coordinates the cyclic exchange of Wnt coregulator complexes at the DNA. These opposing roles of APC and β-catenin permit a rapid coordination of gene expression and cytoskeletal organization throughout the cell in response to signaling.[p]

References to Evo Devo

1990-12-31T00:00:00.000-08:00

Evolution. The synthesis and evolution of a supermodel. [Science. 2005] PMID: 15790836

Evo Devo item: Cited in The evolution of evo-devo biology PNAS April 25, 2000 Vol. 97, Issue 9, 4424-4425:

1.
Conway Morris, S. (2000) Proc. Natl. Acad. Sci. USA 97, 4426-4429[Abstract/Free Full Text].
2.
Peterson, K. J. & Davidson, E. H. (2000) Proc. Natl. Acad. Sci. USA 97, 4430-4433[Abstract/Free Full Text].
3.
Shankland, M. & Seaver, E. C. (2000) Proc. Natl. Acad. Sci. USA 97, 4434-4437[Abstract/Free Full Text].
4.
Akam, M. (2000) Proc. Natl. Acad. Sci. USA 97, 4438-4441[Abstract/Free Full Text].
5.
Patel, N. H. (2000) Proc. Natl. Acad. Sci. USA 97, 4442-4444[Abstract/Free Full Text].
6.
Gerhart, J. (2000) Proc. Natl. Acad. Sci. USA 97, 4445-4448[Abstract/Free Full Text].
7.
Shimeld, S. M. & Holland, P. W. H. (2000) Proc. Natl. Acad. Sci. USA 97, 4449-4452[Abstract/Free Full Text].
8.
Adoutte, A., Balavoine, G., Lartillot, N., Lespinet, O., Prud'homme, B. & de Rosa, R. (2000) Proc. Natl. Acad. Sci. USA 97, 4453-4456[Abstract/Free Full Text].
9.
Chen, J.-Y., Oliveri, P., Li, C.-W., Zhou, G.-Q., Gao, F., Hagadorn, J. W., Peterson, K. J. & Davidson, E. H. (2000) Proc. Natl. Acad. Sci. USA 97, 4457-4462[Abstract/Free Full Text].
10.
Adami, C., Ofria, C. & Collier, T. C. (2000) Proc. Natl. Acad. Sci. USA 97, 4463-4468[Abstract/Free Full Text].
11.
Cameron, C. B., Garey, J. R. & Swalla, B. J. (2000) Proc. Natl. Acad. Sci. USA 97, 4469-4474[Abstract/Free Full Text].
12.
Miller, D. J., Hayward, D. C., Reece-Hoyes, J. S., Scholten, I., Catmull, J., Gehring, W. J., Callaerts, P., Larsen, J. E. & Ball, E. E. (2000) Proc. Natl. Acad. Sci. USA 97, 4475-4480[Abstract/Free Full Text].
13.
Kappen, C. (2000) Proc. Natl. Acad. Sci. USA 97, 4481-4486[Abstract/Free Full Text].
14.
Peterson, K. J., Irvine, S. Q., Cameron, R. A. & Davidson, E. H. (2000) Proc. Natl. Acad. Sci. USA 97, 4487-4492[Abstract/Free Full Text].
15.
Gauchat, D., Mazet, F., Berney, C., Schummer, M., Kreger, S., Pawlowski, J. & Galliot, B. (2000) Proc. Natl. Acad. Sci. USA 97, 4493-4498[Abstract/Free Full Text].
16.
Van Auken, K., Weaver, D. C., Edgar, L. G. & Wood, W. B. (2000) Proc. Natl. Acad. Sci. USA 97, 4499-4503[Abstract/Free Full Text].
17.
Lewis, D. L., DeCamillis, M. & Bennett, R. L. (2000) Proc. Natl. Acad. Sci. USA 97, 4504-4509[Abstract/Free Full Text].
18.
Brown, S., DeCamillis, M., Gonzalez-Charneco, K., Denell, M., Beeman, R., Nie, W. & Denell, R. (2000) Proc. Natl. Acad. Sci. USA 97, 4510-4514[Abstract/Free Full Text].
19.
Damen, W. G. M., Weller, M. & Tautz, D. (2000) Proc. Natl. Acad. Sci. USA 97, 4515-4519[Abstract/Free Full Text].
20.
Sarkar, L., Cobourne, M., Naylor, S., Smalley, M., Dale, T. & Sharpe, P. T. (2000) Proc. Natl. Acad. Sci. USA 97, 4520-4524[Abstract/Free Full Text].
21.
Pineda, D., Gonzalez, J., Callaerts, P., Ikeo, K., Gehring, W. J. & Salo, E. (2000) Proc. Natl. Acad. Sci. USA 97, 4525-4529[Abstract/Free Full Text].
22.
Sucena, É. & Stern, D. L. (2000) Proc. Natl. Acad. Sci. USA 97, 4530-4534[Abstract/Free Full Text].
23.
Graham, L. E., Cook, M. E. & Busse, J. S. (2000) Proc. Natl. Acad. Sci. USA 97, 4535-4540[Free Full Text].

Atheo Devo

1990-01-01T13:40:00.000-08:00

Gray Matters
Adeistic
Avidity
Eine Kleine Nattermusing
eMusings
eVolition
Galaria
Godspell Follies
MetaThoughts
Mimble Wimble
Naturalism
Neologisms
palimpsest
Sechuam
Sintheist
Tabula Flexuosa
Weltschauung

associated

1990-01-01T01:00:00.005-08:00

Associated science sites • Abiogenesis and Evolution • Algorithms of Evolution • Archea Eubacteria • Cancer • Cell Biology • Complex Systems • Cyanobacteria • Diagrams Tables • Endosymbiosis • Enzymes • Evo Devo • Evolution in Action • Fat • Geology • Glossary • Immunology • Life Chemistry • Medical Science • Mechanisms of Evolution • Molecule • Molecular Biology • Molecular Paths • Neurosciences • Organics • Origin of Life • Paleogeology • Pathways • Photosynthesis • Protein • Receptor • Rocks & Minerals • SET • Signaling • Sleep • Stem & Progenitor Cells • Stromatolites • Taxonomy Phylogeny • Tissue • Virus •

And some philosophy/general interest sites: Avidity : Eine Kleine Nattermusing : eMusings : Galaria : Godspell Follies : Harper's Folly : Mimble Wimble : Sintheist : Tabula Flexuosa :

ooo

1990-01-01T01:00:00.004-08:00

• Abiogenesis and Evolution • Algorithms of Evolution • Archea Eubacteria • Cancer • Cell Biology • Complex Systems • Cyanobacteria • Diagrams Tables • Endosymbiosis • Enzymes • Evo Devo • Evolution in Action • Fat • Geology • Galaria • Glossary • Godspell Follies • Harper's Folly • Immunology • Life Chemistry • Medical Science • Mechanisms of Evolution • Mimble Wimble • Molecule • Molecular Biology • Molecular Paths • Organics • Origin of Life • Paleogeology • Pathways • Photosynthesis • Protein • Receptor • Rocks & Minerals • SET • Signaling • Sleep • Stem & Progenitor Cells • Stromatolites • Tabula Flexuosa • Taxonomy Phylogeny • Tissue • Virus •

SITE MAP

1990-01-01T00:00:00.000-08:00

Order of items on site:

₪ Evo Devo ₪ alternative exons ₪ Alu elements ₪ alternative promoters ₪ alternative splicing ₪ alternative 3' splicing ₪ alternative 5' splicing ₪ cassette exons ₪ cellular fate ₪ cell cycle ₪ cellular survival ₪ differentiation & embryogenesis ₪ epigenetic mechanisms ₪ ESE ₪ ESS ₪ exon skipping ₪ gene regulation and biological evolution ₪ genetic variation ₪ homeobox genes ₪ homeodomain ₪ intron retention ₪ ISE ₪ ISS ₪ micro RNA ₪ molecular switches ₪ regulation ₪ signaling ₪ Wnt signaling ₪ References to Evo Devo ₪ SITE MAP ₪ Companion Sites

Alphabetic items: items may be listed more than once under alternate names: ₪ alternative exons ₪ alternative promoters ₪ alternative splicing ₪ alternative 3' splicing ₪ alternative 5' splicing ₪ Alu elements ₪ biological evolution through gene regulation ₪ cassette exons ₪ cell cycle ₪ cell signaling ₪ cellular fate ₪ cellular survival ₪ Companion Sites ₪ communication ₪ cycle ₪ differentiation & embryogenesis ₪ epigenetic mechanisms ₪ ESE ₪ ESE, ESS, ISE, ISS ₪ ESS ₪ Evo Devo ₪ exon skipping ₪ gene regulation and biological evolution ₪ genetic variation ₪ homeobox genes ₪ homeodomain ₪ intron retention ₪ ISE ₪ ISS ₪ micro RNA ₪ molecular switches ₪ References to Evo Devo ₪ regulation ₪ regulation of genes and biological evolution ₪ signaling ₪ switches ₪ variation ₪
.