Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Budding yeast strains have three CLN genes, which have limited cyclin homology. At least one of the three is required for cell cycle START. Four B cyclins are known in yeast; two have been shown to function in mitosis. We have discovered a fifth B-cyclin gene, called CLB5, which when cloned on a CEN plasmid can rescue strains deleted for all three CLN genes. CLB5 transcript abundance peaks in G1, coincident with the CLN2 transcript but earlier than the CLB2 transcript. CLB5 deletion does not cause lethality, either alone or in combination with other CLN or CLB deletions. However, strains deleted for CLB5 require more time to complete S phase, suggesting that CLB5 promotes some step in DNA synthesis. CLB5 is the only yeast cyclin whose deletion lengthens S phase. CLB5 may also have some role in promoting the G1/S transition, because cln1 cln2 strains require both CLN3 and CLB5 for viability on glycerol media and cln1,2,3- strains require CLB5 for rescue by the Drosophila melanogaster cdc2 gene. In conjunction with cln1,2,3- rescue by CLB5 overexpression and the coincident transcriptional regulation of CLB5 and CLN2, these observations are suggestive of partial functional redundancy between CLB5 and CLN genes.
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PMID:CLB5: a novel B cyclin from budding yeast with a role in S phase. 138 26

We have isolated two Drosophila cDNA clones that rescue Saccharomyces cerevisiae deficient in CLN functions. One of these clones is the Drosophila homolog of the cdc2 gene. The second encodes a distant and new member of the cyclin family of proteins, cyclin C. It is highly homologous (72% identity) to a human clone isolated in a similar screen. Yeast cells rescued by a plasmid constitutively expressing this Drosophila cyclin C are unusually small, consistent with an unregulated high level of G1 cyclin function. Sequence comparisons identified regions conserved among the more distantly related cyclins. Based on these conserved elements, we identified homology between cyclins and the ras oncogene.
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PMID:An evolutionarily conserved cyclin homolog from Drosophila rescues yeast deficient in G1 cyclins. 183 67

Cyclin E is a regulatory subunit of the cdc2-related protein kinase cdk2, which is activated shortly before S-phase entry, thus defining it as a G1 cyclin. We report here the existence of a 43 kDa splice variant of human cyclin E, termed cyclin Es, which lacks 49 amino acids within the cyclin box compared to the known 48 kDa cyclin E. Cyclin Es is expressed at approximately 1/10 of the level of full-length cyclin E in several cell lines analysed. The two cyclin E forms differ functionally in that cyclin E, but not cyclin Es, is able to complex with cdk2, to activate the histone H1, pRb and p107 in vitro kinase activity of cdk2 and to rescue a triple CLN mutation in S. cerevisiae. Cyclin Es is the first splice variant of a cell cycle regulatory protein to be described. Our findings also indicate that the cyclin box in cyclin E mediates the interaction with cdk2.
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PMID:Alternative splicing of human cyclin E. 820 80

Traversal from G1 to S-phase in cycling cells of budding yeast is dependent on the destruction of the S-phase cyclin/CDK inhibitor SIC1. Genetic data suggest that SIC1 proteolysis is mediated by the ubiquitin pathway and requires the action of CDC34, CDC4, CDC53, SKP1, and CLN/CDC28. As a first step in defining the functions of the corresponding gene products, we have reconstituted SIC1 multiubiquitination in DEAE-fractionated yeast extract. Multiubiquitination depends on cyclin/CDC28 protein kinase and the CDC34 ubiquitin-conjugating enzyme. Ubiquitin chain formation is abrogated in cdc4ts mutant extracts and assembly restored by the addition of exogenous CDC4, suggesting a direct role for this protein in SIC1 multiubiquitination. Deletion analysis of SIC1 indicates that the N-terminal 160 residues are both necessary and sufficient to serve as substrate for CDC34-dependent ubiquitination. The complementary C-terminal segment of SIC1 binds to the S-phase cyclin CLB5, indicating a modular structure for SIC1.
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PMID:SIC1 is ubiquitinated in vitro by a pathway that requires CDC4, CDC34, and cyclin/CDK activities. 928 16

We show that a splice variant-derived cyclin B is produced in sea urchin oocytes and embryos. This splice variant protein lacks highly conserved sequences in the COOH terminus of the protein. It is found strikingly abundant in growing oocytes and cells committed to differentiation during embryogenesis. Cyclin B splice variant (CBsv) protein associates weakly in the cell with Xenopus cdc2 and with budding yeast CDC28p. In contrast to classical cyclin B, CBsv very poorly complements a triple CLN deletion in budding yeast, and its microinjection prevents an initial step in MPF activation, leading to an important delay in oocyte meiosis reinitiation. CBsv microinjection in fertilized eggs induces cell cycle delay and abnormal development. We assume that CBsv is produced in growing oocytes to keep them in prophase, and during embryogenesis to slow down cell cycle in cells that will be committed to differentiation.
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PMID:A presumptive developmental role for a sea urchin cyclin B splice variant. 944 4

In Saccharomyces cerevisiae, mating pheromones activate two MAP kinases (MAPKs), Fus3p and Kss1p, to induce G1 arrest prior to mating. Fus3p is known to promote G1 arrest by activating Far1p, which inhibits three Clnp/Cdc28p kinases. To analyze the contribution of Fus3p and Kss1p to G1 arrest that is independent of Far1p, we constructed far1 CLN strains that undergo G1 arrest from increased activation of the mating MAP kinase pathway. We find that Fus3p and Kss1p both control G1 arrest through multiple functions that operate in parallel with Far1p. Fus3p and Kss1p together promote G1 arrest by repressing transcription of G1/S cyclin genes (CLN1, CLN2, CLB5) by a mechanism that blocks their activation by Cln3p/Cdc28p kinase. In addition, Fus3p and Kss1p counteract G1 arrest through overlapping and distinct functions. Fus3p and Kss1p together increase the expression of CLN3 and PCL2 genes that promote budding, and Kss1p inhibits the MAP kinase cascade. Strikingly, Fus3p promotes proliferation by a novel function that is not linked to reduced Ste12p activity or increased levels of Cln2p/Cdc28p kinase. Genetic analysis suggests that Fus3p promotes proliferation through activation of Mcm1p transcription factor that upregulates numerous genes in G1 phase. Thus, Fus3p and Kss1p control G1 arrest through a balance of arrest functions that inhibit the Cdc28p machinery and proliferative functions that bypass this inhibition.
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PMID:Fus3p and Kss1p control G1 arrest in Saccharomyces cerevisiae through a balance of distinct arrest and proliferative functions that operate in parallel with Far1p. 1004 17

To identify cyclin-dependent kinase mutants with relaxed cyclin requirements, CDC28 alleles were selected that could rescue a yeast strain expressing as its only CLN G1 cyclin a mutant Cln2p (K129A,E183A) that is defective for Cdc28p binding. Rescue of this strain by mutant CDC28 was dependent upon the mutant cln2-KAEA, but additional mutagenesis and DNA shuffling yielded multiply mutant CDC28-BYC alleles (bypass of CLNs) that could support highly efficient cell cycle initiation in the complete absence of CLN genes. By gel filtration chromatography, one of the mutant Cdc28 proteins exhibited kinase activity associated with cyclin-free monomer. Thus, the mutants' CLN bypass activity might result from constitutive, cyclin-independent activity, suggesting that Cdk targeting by cyclins is not required for cell cycle initiation.
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PMID:Directed evolution to bypass cyclin requirements for the Cdc28p cyclin-dependent kinase. 1051 16

Two Trypanosoma brucei cyclin genes, CYC2 and CYC3, have been isolated by rescue of the Saccharomyces cerevisiae mutant DL1, which is deficient in CLN G(1) cyclin function. CYC2 encodes a 24-kDa protein that has sequence identity to the Neurospora crassa PREG1 and the S. cerevisiae PHO80 cyclin. CYC3 has the most sequence identity to mitotic B-type cyclins from a variety of organisms. Both CYC2 and CYC3 are single-copy genes and expressed in all life cycle stages of the parasite. To determine if CYC2 is found in a complex with previously identified trypanosome cdc2-related kinases (CRKs), the CYC2 gene was fused to the TY epitope tag, integrated into the trypanosome genome, and expressed under inducible control. CYC2ty was found to associate with an active trypanosome CRK complex since CYC2ty bound to leishmanial p12(cks1), and histone H1 kinase activity was detected in CYC2ty immune-precipitated fractions. Gene knockout experiments provide evidence that CYC2 is an essential gene, and co-immune precipitations together with a two-hybrid interaction assay demonstrated that CYC2 interacts with CRK3. The CRK3 x CYC2ty complex, the first cyclin-dependent kinase complex identified in trypanosomes, was localized by immune fluorescence to the cytoplasm throughout the cell cycle.
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PMID:Isolation of Trypanosoma brucei CYC2 and CYC3 cyclin genes by rescue of a yeast G(1) cyclin mutant. Functional characterization of CYC2. 1072 61

Recently, we identified two Trpanosoma brucei cyclin genes, CYC2 and CYC3, by rescue of the Saccharomyces cerevisiae mutant DL1, which is deficient in CLN G1 cyclin function. CYC3 has a low level of sequence identity to mitotic B-type cyclins from a variety of organisms. In order to examine whether CYC3 associates in vivo with a trypanosome cdc2-related kinase (CRK), the CYC3 gene was fused with the TY-epitope tag, integrated into the trypanosome genome and expressed under inducible control. CYC3ty was demonstrated to associate with the CRK-binding factor p12cks1 and histone H1 kinase activity could be detected in CYC3ty immune precipitated fractions, which demonstrates that CYC3ty associates in vivo with an active trypanosome CRK. Both CYC3ty and CYC2ty were shown to have a half-life of less than one cell cycle, which was significantly elongated by specific proteasome inhibitors, strongly suggesting that CYC3ty and CYC2ty are substrates for proteasome degradation. This is consistent with the presence in CYC3 of a putative destruction box motif that defines proteins for degradation via the ubiquitin degradation pathway. These results are consistant with proteolysis by the proteasome being involved in regulation of the cellular cyclin concentration in trypanosomes.
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PMID:The CYC3 gene of trypanosoma brucei encodes a cyclin with a short half-life. 1116 36