High impact information on cdc2

• In mammalian cells, LATS1 is phosphorylated in a cell-cycle-dependent manner and complexes with CDC2 in early mitosis [1].
• We propose that cyclin A-cdc2 kinase at the G2 to M transition of meiosis I activates a target necessary for meiosis II, thereby coupling the two meiotic divisions [2].
• Mutations in E(sev)3B also dominantly enhance mutations in Dmcdc2, the gene encoding the p34 protein kinase that regulates the G2/M transition [3].
• Finally, the phenotypes observed suggest that the cdc 10/ankyrin repeat region within the intracellular domain plays an essential role in the postulated signal transduction events [4].
• Genetic and biochemical studies have indicated that the cdc25 protein controls the entry into mitosis by triggering tyrosine dephosphorylation of the cdc2 protein kinase [5].

Biological context of cdc2

• Here we show that neural progenitor asymmetric divisions require the cell-cycle regulator cdc2 [6].
• The gene that encodes the Drosophila cdc2 homologue maps to a single locus in the Drosophila genome at 31E on chromosome 2 [7].
• This library was introduced into S.pombe cdc2 and cdc25 mutants, and plasmids isolated carrying cDNAs that complement these mutations [7].
• Deletion of these sequences is correlated with loss of Gro/TLE phosphorylation by cdc2 in vitro and okadaic acid-induced Gro/TLE hyperphosphorylation in vivo [8].
• Deficiencies that removed one of the Drosophila cdc2 genes and the cyclin A gene had no effect on replication during embryogenesis [9].

Anatomical context of cdc2

• This suggests that the major mechanism of suppression relies on the interactions among Cdk1-CycB, microtubule, and microfilament networks [10].
• A genetic screen for suppressors and enhancers of the Drosophila cdk1-cyclin B identifies maternal factors that regulate microtubule and microfilament stability [10].
• Three B-cyclins in Drosophila, Cyclins (Cyc) A, B, and B3, associate with CDK1 and play partially redundant roles in embryogenic mitosis . Here, we show that the division of Drosophila GSCs and their precursors, the primordial germ cells (PGCs), specifically requires CycB [11].
• The cdc2+ gene product (p34cdc2) is a protein kinase that regulates entry into mitosis in all eukaryotic cells [12].
• This pattern of Cdk1 inactivation would be consistent with local cyclin destruction at centrosomes or kinetochores [13].

Associations of cdc2 with chemical compounds

• As a prerequisite for the activation of MPF, the cdc2 protein kinase must undergo tyrosine dephosphorylation [14].
• In the study reported in this paper, we have used co-immunoprecipitation and confocal microscopy to demonstrate that tuberin interacts with and co-localizes with CDK1 and its binding partner cyclin B1 in multiple cell types [15].
• A short NH2-terminal domain contains adjacent consensus sequences for nuclear localization and cdc2 kinase phosphorylation [16].
• A major site for cdc2 kinase phosphorylation in vitro was mapped to serine 36 of otefin [17].
• Otefin is a phosphoprotein in vivo and is a substrate for in vitro phosphorylation by cdc2 kinase and cyclic AMP-dependent protein kinase [17].

Physical interactions of cdc2

• Cdc2 binds to E2F in vitro, and post-transcriptionally promotes its accumulation in vivo [18].
• During cell cycles 2-7, Cdc2/Cyclin complexes are continuously present and show little fluctuation in abundance, phosphomodification, or activity [19].

Enzymatic interactions of cdc2

• Wee1 kinases catalyze inhibitory phosphorylation of the mitotic regulator Cdk1, preventing mitosis during S phase and delaying it in response to DNA damage or developmental signals during G2 [20].

Regulatory relationships of cdc2

• We present biochemical, cytological and genetic data indicating that Mei-41 and Grapes are components of a conserved DNA-replication/damage checkpoint pathway that triggers inhibitory phosphorylation of the Cdc2 kinase and mediates resistance to replication inhibitors and DNA-damaging agents [21].
• Drosophila Wee1 kinase regulates Cdk1 and mitotic entry during embryogenesis [22].
• RESULTS: We show that Cdc2 co-expressed with Cyclin A inhibits the S phase in Drosophila salivary glands and diploid abdominal histoblasts [18].
• Furthermore, a mutant form of the mitotic kinase Cdk1 that cannot be inhibited by phosphorylation drove a mitotic cyclin into the nucleus and overcame the delay of mitosis induced by irradiation [23].
• The same phenotype was also observed in twine and twine, Dmcdc2ts double mutant testes, consistent with the idea that the cdc2 kinase activity required for meiotic divisions is activated by the Twine/cdc25 phosphatase [24].

Other interactions of cdc2

• Surprisingly, Rux had a stimulating effect on CycA-Cdk1 activity when present in low concentrations [25].
• Since it has been shown that active cdc2 is required to maintain the arrest seen in fzy embryos we wished to determine if pim+ and thr+ were also required [26].
• Cdk1 inhibition by Rux did not rely on inhibitory phosphorylation, disruption of cyclin-Cdk complex formation or changes in subcellular localization [25].
• Our findings link cdc2 with asymmetric divisions, and explain why the asymmetric localization of molecules like Inscuteable show cell-cycle dependence [6].
• The corresponding sites in the closely related Cdk1 (Thr 14 and Tyr 15) are of crucial importance for regulation of the G2/M transition by myt1 and wee1 kinases and cdc25 phosphatases [27].

Analytical, diagnostic and therapeutic context of cdc2

• Southern blot experiments and in situ hybridization to polytene chromosomes demonstrated that the isolated cDNAs, were derived from two distinct genes, Dm cdc2 (31E) and Dm cdc2c (92F) [28].
• In vivo tests of L63 proteins altered by site-directed mutagenesis showed that they exhibit CDK functions [29].

References