Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The events of the eukaryotic cell cycle are governed by cyclin-dependent kinases (cdk's), whose activation requires association with cyclin regulatory subunits expressed at specific cell cycle stages. In the budding yeast Saccharomyces cerevisiae, the cell cycle is thought to be controlled by a single cdk, CDC28. Passage through the G1 phase of the cell cycle is regulated by complexes of CDC28 and G1 cyclins (CLN1, CLN2, and CLN3). A putative G1 cyclin, HCS26, has recently been identified. In a/alpha diploid cells lacking CLN1 and CLN2, HCS26 is required for passage through G1. HCS26 does not associate with CDC28, but instead associates with PHO85, a closely related protein kinase. Thus, budding yeast, like higher eukaryotes, use multiple cdk's in the regulation of cell cycle progression.
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PMID:Cell cycle control by a complex of the cyclin HCS26 (PCL1) and the kinase PHO85. 797 30

It is thought that DNA replication and mitosis in yeast are triggered by oscillations in the level of G1-specific (CLN1 and CLN2) and G2-specific (CLB1-CLB4) cyclins, which determine the substrate specificity of the CDC28 protein kinase. It is not understood how the time and order of appearance of different cyclin types are determined. We show here that CLB2 proteolysis, which is important for transition from mitosis to G1, is not confined to a narrow window at the end of mitosis as previously thought but continues until reactivation of CDC28 by CLN cyclins toward the end of the subsequent G1 period. Thus, cell cycle-regulated proteolysis prevents accumulation of G2-specific CLB cyclins during G1 and thereby ensures that the CLN-associated forms of the CDC28 kinase are activated without interference from CLB cyclins. Accumulation of CLN cyclins leads to inactivation of CLB cyclin proteolysis, which is a precondition for subsequent activation of G2-specific B-type cyclins.
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PMID:Closing the cell cycle circle in yeast: G2 cyclin proteolysis initiated at mitosis persists until the activation of G1 cyclins in the next cycle. 802 94

A yeast cell becomes committed to the cell division cycle only if it grows to a critical size and reaches a critical rate of protein synthesis. The coordination between growth and division takes place at a control step during the G1 phase of the cell cycle called Start. It relies on the G1-specific cyclins encoded by CLN1, 2 and 3, which trigger Start through the activation of the Cdc28 protein kinase. In fact, the Cln cyclins are rate-limiting for Start execution and depend on growth. Here we report that the cyclic AMP signal pathway modulates the dependency of Cln cyclins on growth. In particular, more growth is required to trigger Start because CLN1 and CLN2 are repressed by the cAMP signal, thus explaining the previously observed cAMP-dependent increase of the critical size and critical rate of protein synthesis. Cln3 is not inhibited by the cAMP pathway and counteracts this mechanism by partially mediating the growth-dependent expression of other G1 cyclins.
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PMID:Repression of growth-regulated G1 cyclin expression by cyclic AMP in budding yeast. 809 Jan 97

In the yeast Saccharomyces cerevisiae, commitment to cell division (Start) requires growth to a critical cell size. The G1 cyclins Cln1, Cln2 and Cln3 activate the Cdc28 protein kinase and are rate-limiting activators of Start. When glucose is added to cells growing in a poor carbon source, the critical cell size required for Start is reset from a small to a large size. In yeast, glucose acts through Ras proteins to stimulate adenylyl cyclase, activating the three cyclic AMP-dependent protein kinases Tpk1, Tpk2 and Tpk3 (refs 8, 9). We find that stimulation of the Ras/cAMP pathway represses expression of CLN1, CLN2 and co-regulated genes, inhibiting Start. This helps explain the increase in critical size when cells are shifted from poor to rich medium. This connection between the molecules controlling growth (Ras/cAMP) and those controlling division (cyclins) helps explain how division is co-ordinated with growth.
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PMID:Inhibition of G1 cyclin activity by the Ras/cAMP pathway in yeast. 809 Jan 97

Unlike early embryonic cleavage divisions in certain animals, cell-cycle progression in yeast and probably also in all metazoan somatic cells requires the periodic transcriptional activation of certain key genes. Thus far, the only clear examples are genes that encode a class of unstable 'cyclin' proteins, which bind and activate the cdc2/Cdc28 protein kinase: the G1-specific cyclins encoded by CLN1 and CLN2, a B-type cyclin implicated in DNA replication encoded by CLB5; and four B-type cyclins involved in mitosis encoded by CLB1, 2, 3, 4. CLN1, CLN2, and CLB5 are transcribed in late G1, as cells undergo Start. A transcription factor composed of Swi4 and Swi6 proteins (called SBF) activates CLN1 and CLN2 transcription via a positive feedback loop in which Cln proteins activate their own transcription. A different but related transcription factor called MBF seems responsible for the late G1-specific transcription of most DNA replication genes including CLB5. We have purified MBF and shown that it contains Swi6 and a 110-120 kDa protein distinct from Swi4 (p120) that contacts DNA. Thus, we propose that SBF and MBF share a common regulatory subunit (Swi6) but recognize their promoter elements via distinct DNA binding subunits.
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PMID:Transcription factors important for starting the cell cycle in yeast. 810 39

The CLN1, CLN2 and CLN3 gene family of G1-acting cyclin homologs of Saccharomyces cerevisiae is functionally redundant: any one of the three Cln proteins is sufficient for activation of Cdc28p protein kinase activity for cell cycle START. The START event leads to multiple processes (including DNA replication and bud emergence); how Cln/Cdc28 activity activates these processes remains unclear. CLN3 is substantially different in structure and regulation from CLN1 and CLN2, so its functional redundancy with CLN1 and CLN2 is also poorly understood. We have isolated mutations that alter this redundancy, making CLN3 insufficient for cell viability in the absence of CLN1 and CLN2 expression. Mutations causing phenotypes specific for the cell division cycle were analyzed in detail. Mutations in one gene result in complete failure of bud formation, leading to depolarized cell growth. This gene was identified as BUD2, previously described as a non-essential gene required for proper bud site selection but not required for budding and viability. Bud2p is probably the GTPase-activating protein for Rsr1p/Bud1p [Park, H., Chant, I. and Herskowitz, I. (1993) Nature, 365, 269-274]; we find that Rsr1p is required for the bud2 lethal phenotype. Mutations in two other genes (ERC10 and ERC19) result in a different morphogenetic defect: failure of cytokinesis resulting in the formation of long multinucleate tubes. These results suggest direct regulation of diverse aspects of bud morphogenesis by Cln/Cdc28p activity.
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PMID:Genetic analysis of Cln/Cdc28 regulation of cell morphogenesis in budding yeast. 826 69

The functions of the Cdc28 protein kinase in DNA replication and mitosis in Saccharomyces cerevisiae are thought to be determined by the type of cyclin subunit with which it is associated. G1-specific cyclins encoded by CLN1, CLN2, and CLN3 are required for entry into the cell cycle (Start) and thereby for S phase, whereas G2-specific B-type cyclins encoded by CLB1, CLB2, CLB3, and CLB4 are required for mitosis. We describe a new family of B-type cyclin genes, CLB5 and CLB6, whose transcripts appear in late G1 along with those of CLN1, CLN2, and many genes required for DNA replication. Deletion of CLB6 has little or no effect, but deletion of CLB5 greatly extends S phase, and deleting both genes prevents the timely initiation of DNA replication. Transcription of CLB5 and CLB6 is normally dependent on Cln activity, but ectopic CLB5 expression allows cells to proliferate in the absence of Cln cyclins. Thus, the kinase activity associated with Clb5/6 and not with Cln cyclins may be responsible for S-phase entry. Clb5 also has a function, along with Clb3 and Clb4, in the formation of mitotic spindles. Our observation that CLB5 is involved in the initiation of both S phase and mitosis suggests that a single primordial B-type cyclin might have been sufficient for regulating the cell cycle of the common ancestor of many, if not all, eukaryotes.
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PMID:CLB5 and CLB6, a new pair of B cyclins involved in DNA replication in Saccharomyces cerevisiae. 831 8

In the budding yeast Saccharomyces cerevisiae, the G1 cyclins Cln1, Cln2 and Cln3 regulate entry into the cell cycle (Start) by activating the Cdc28 protein kinase. We find that Cln3 is a much rarer protein than Cln1 or Cln2 and has a much weaker associated histone H1 kinase activity. Unlike Cln1 and Cln2, Cln3 is not significantly cell cycle regulated, nor is it down-regulated by mating pheromone-induced G1 arrest. An artificial burst of CLN3 expression early in G1 phase accelerates Start and rapidly induces at least five other cyclin genes (CLN1, CLN2, HCS26, ORFD and CLB5) and the cell cycle-specific transcription factor SWI4. In similar experiments, CLN1 is less efficient than CLN3 at activating Start. Strikingly, expression of HCS26, ORFD and CLB5 is dependent on CLN3 in a cln1 cln2 strain, possibly explaining why CLN3 is essential in the absence of CLN1 and CLN2. To explain the potent ability of Cln3 to activate Start, despite its apparently weak biochemical activity, we propose that Cln3 may be an upstream activator of the G1 cyclins which directly catalyze Start. Given the large number of known cyclins, such cyclin cascades may be a common theme in cell cycle control.
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PMID:Comparison of the Saccharomyces cerevisiae G1 cyclins: Cln3 may be an upstream activator of Cln1, Cln2 and other cyclins. 838 15

Cyclins regulate the major cell cycle transitions in eukaryotes through association with cyclin-dependent protein kinases (CDKs). In yeast, G1 cyclins are essential, rate-limiting activators of cell cycle initiation. G1-specific accumulation of one G1 cyclin, Cln2, results from periodic gene expression coupled with rapid protein turnover. Site-directed mutagenesis of CLN2 revealed that its phosphorylation provides a signal that promotes rapid degradation. Cln2 phosphorylation is dependent on the Cdc28 protein kinase, the CDK that it activates. These findings suggest that Cln2 is rendered self-limiting by virtue of its ability to activate its cognate CDK subunit.
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PMID:Rapid degradation of the G1 cyclin Cln2 induced by CDK-dependent phosphorylation. 859 19

In a genetic screen for second-site mutations that are lethal in combination with a deletion of the amino terminus of histone H3, we have uncovered three new gene products that regulate the Saccharomyces cerevisiae Swe1 kinase. The Swe1 protein kinase phosphorylates tyrosine residue 19 of Cdc28 and inhibits its activity. One histone synthetic-lethal gene, HSL1, encodes a putative protein kinase that has high sequence and functional homology to fission yeast cdr1/nim1, an inhibitory kinase of wee1. Another gene, HSL7, is a novel negative regulator of Swe1 function. Sequences similar to Hsl7 exist in Caenorhabditis elegans and humans. In addition, we have isolated a dosage-dependent suppressor, OSS1, of hsl1 and hsl7. OSS1 is important for the transcriptional repression of SWE1 and CLN2 in G2. Mutations in HSL1 and HSL7 therefore cause hyperactivity of the Swe1 kinase, which in turn decreases mitotic Cdc28 kinase activity. Moreover, HSL5 is identical to CDC28, further suggesting that it is the decreased Cdc28 kinase activity in these hsl mutants that causes lethality in the histone mutant background. Because neither HSL1 nor HSL7 is essential in yeast, and histone transcription is unaffected by the hsl5/cdc28 mutation, it is unlikely that synthetic lethality results from reduced transcription of HSL1 and HSL7 caused by histone mutations, or from reduced histone transcription when Cdc28 kinase activity is compromised. We suggest that these cell cycle regulators function in a pathway upstream of both histones H3 and H4, thereby modulating histone function in the cell cycle.
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PMID:A search for proteins that interact genetically with histone H3 and H4 amino termini uncovers novel regulators of the Swe1 kinase in Saccharomyces cerevisiae. 864 31


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