Disease relevance of cdc2

• Ethanol sensitivity was also tested in strains bearing different alleles of the cdc2 gene, and we found that some of them were ets, but others were non-ets; thus, ethanol hypersensitivity is an allele-specific phenotype [1].

High impact information on cdc2

• The wee1 tyrosine kinase and cdc25 tyrosine phosphatase of fission yeast play antagonistic roles in the induction of mitosis through cdc2 regulation [2].
• We show here that the human wee1-like tyrosine kinase is a nuclear protein that ensures the completion of DNA replication prior to mitosis in cells expressing otherwise catastrophic levels of cdc2 activators [2].
• mik1 and wee1 cooperate in the inhibitory tyrosine phosphorylation of cdc2 [3].
• The data suggest that mik1 and wee1 act cooperatively on cdc2, either directly as the inhibitory tyrosine kinase or as essential activators of that kinase [3].
• Activation of the preformed cdc2/cdc13 complex at the G2/M transition requires cdc25+ gene function [4].

Biological context of cdc2

• Similarly, in fission yeast, the cdc25 and cdc2 gene products influence the ability of cells to delay mitosis in response to the inhibition of DNA synthesis [5].
• The activity of p34cdc2 is controlled, in part, by the wee1 protein kinase, which inactivates cdc2 through phosphorylation at tyrosine-15 (ref. 7). Here we report normal mitotic arrest after DNA damage in S. pombe cells in which the wee1 gene is defective or missing [6].
• A quantitative model for the cdc2 control of S phase and mitosis in fission yeast [7].
• First, mcs2 cdc2w or mcs6 cdc2w double mutants display a cell cycle defect dependent on the specific wee allele of cdc2 [8].
• The gene dosage of wee1+ plays some role in determining the timing of mitosis, but the gene dosage of cdc2+ has little effect [9].

Anatomical context of cdc2

• The cdc2 protein kinase, first identified as a cell cycle gene required for transition into the S- and M-phases of budding and fission yeast, has been shown to act as a key component in the regulation of the eukaryotic cell cycle [10].
• These results suggest a key regulatory role of the cdc2-cyclin complex in the initiation of mitotic spindle formation and also that mitotic microtubule function is required for cdc2 activation [11].
• Resting murine T lymphocytes contained no detectable p34cdc2 protein, histone kinase activity, or specific mRNA for the cdc2 gene [12].
• Maturation-promoting factor and a homolog of fission yeast cdc2+ gene product (p34cdc2) were investigated during the final 24 hr of maturation of quail oocytes [13].

Associations of cdc2 with chemical compounds

• Eukaryotic cell cycle progression requires the periodic activation and inactivation of a protein-serine/threonine kinase which in fission yeast is encoded by the cdc2+ gene [14].
• Phospho-T was abolished in the alanine substitution mutant at the C-terminal T316, which is conserved as a residue in the cdc2 consensus, TPPR, in a number of type 1-like phosphatases [15].
• Despite this, the caffeine-induced loss of viability was not blocked in a temperature-sensitive cdc2 mutant incubated at the restrictive temperature, although catastrophic mitosis was prevented under these conditions [16].
• The kinase domains are approximately 50-55% homologous to members of the cdc2/CDC28 kinase gene family, and each contains a cysteine-for-serine substitution within the conserved PSTAIRE motif [17].
• The product of the cdc2+ gene is a 34-kDa serine/threonine protein kinase, designated p34cdc2, that is a component of purified maturation-promoting factor (MPF) and also of purified mammalian growth-associated histone H1 kinase [18].

Physical interactions of cdc2

• Phosphorylation at Tyr 15 inhibits activation of the cdc2/cdc13 complex whereas phosphorylation of Thr 167 is required for kinase activity [10].
• Whilst p25rum1 can inhibit cig2/cdc2 activity in vitro, and may transiently inhibit this complex in vivo, cig1 is regulated independently of p25rum1 [19].
• During interphase the cdc2/cyclin complex is assembled in an inactive state that requires cdc25+ gene function for M-phase activation [20].

Enzymatic interactions of cdc2

• The fission yeast cdr1/nim1 protein kinase phosphorylates and inactivates the weel cdc2-inhibitory kinase [21].

Regulatory relationships of cdc2

• Genetic evidence indicates that wee1+ and cdc25+ compete in a control system regulating the cdc2+ protein kinase, which is required for mitotic initiation [22].
• We also show that ste9/srw1 is negatively regulated by cdc2-dependent protein phosphorylation [23].
• Treatment of cells with the antimicrotubule drug thiabendazole prevents cyclin degradation and blocks the tyrosine dephosphorylation and activation of cdc2 [11].
• A DNA fragment called suc1 has been found to rescue cells mutated in the cell cycle control gene cdc2 of the fission yeast Schizosaccharomyces pombe [24].
• The cmk2(+) gene is not essential for cell viability but overexpression of cmk2(+) blocks the cell cycle at G2 phase and this inhibition is cdc2-dependent [25].

Other interactions of cdc2

• The simplest interpretation of these observations is that wee1+ codes for a negative element or inhibitor, and cdc2+ codes for a positive element or activator in the mitotic control [9].
• Novel alleles of cdc13 and cdc2 isolated as suppressors of mitotic catastrophe in Schizosaccharomyces pombe [26].
• The onset of mitosis is governed by cdc2 in partnership with the B-type cyclin, cdc13 [7].
• The fission yeast cdc2/cdc13/suc1 protein kinase: regulation of catalytic activity and nuclear localization [4].
• Activity of Start genes cdc2 and cdc10 is necessary and p34cdc2 kinase is active in re-replicating cells [27].

Analytical, diagnostic and therapeutic context of cdc2

• Northern and Western blotting detection reveals that unlike cdc25B, cdc25C and cdc2, cdc25A is predominantly expressed in late G1 [28].
• Reverse transcriptase PCR confirmed the inability of the S. pombe cdc2 mutants to splice the P. carinii genomic cdc2 [29].
• A 38 kb segment containing the cdc2 gene from the left arm of fission yeast chromosome II: sequence analysis and characterization of the genomic DNA and cDNAs encoded on the segment [30].
• Northern blotting results shows that Paramecium cdc2 is much more expressed in actively dividing cells [31].
• Southern blot analysis indicates that Paramecium has multiple cdc2 genes [31].

References