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Ninomiya-Tsuji et al. (1991) cloned 2 different cDNAs that can complement cdc28 mutations of budding yeast Saccharomyces cerevisiae. One corresponded to a gene encoding human p34(CDC2) kinase (116940), and the other to a gene that had not been characterized previously, CDK2 (cell division kinase-2). The CDK2 protein was highly homologous to p34(CDC2) kinase and more significantly homologous to Xenopus Eg1 kinase, suggesting that CDK2 is the human homolog of Eg1. The human CDC2 and CDK2 genes were both able to complement the inviability of a null allele of S. cerevisiae, CDC28. However, CDK2 was unable to complement cdc2 mutants in fission yeast Schizosaccharomyces pombe under the condition where the human CDC2 gene could complement them. CDK2 mRNA appeared late in G1 or in early S phase, slightly before CDC2 mRNA, after growth stimulation in the normal human fibroblast cells. Thus, 2 different CDC2-like kinases appear to regulate the human cell cycle at different stages.
The complex formed of p34(cdc2) (116940) and cyclin B (176740) is required for the G2-to-M transition in cell division. Human cyclin A (123835) binds independently to 2 kinases, p34(cdc2) or p33. In adenovirus-transformed cells, the viral E1A oncoprotein seems to associate with p33/cyclin A but not with p34(cdc2)/cyclin A. Tsai et al. (1991) isolated the gene for p33, which shares 65% sequence identity with p34(cdc2). They suggested that p33(cdk2) plays a unique role in cell cycle regulation of vertebrate cells.
De Bondt et al. (1993) reported the crystal structure of CDK2. Bourne et al. (1996) analyzed the crystal structure of the CDK-CKS1 complex and defined the critical protein domains involved in the interaction of the 2 molecules. They tested the biologic importance of the structure-based model by constructing mutant alleles of CKS1 that led to decreased interaction with CDK2. Bourne et al. (1996) concluded that the structural analysis revealed the mode of CDK2 binding to CKS1, suggested a possible mechanism of cooperativity and self regulation of CKS proteins during the cell cycle, and implicated CKS as a targeting or matchmaking protein for CDK and at least one other phosphoprotein. Jeffrey et al. (1995) determined the physical structure of the human cyclin A-CDK2-ATP complex at 2.3-angstrom resolution. Cyclin A was found to bind to one side of CDK2's catalytic cleft, inducing large conformational changes that activate the kinase by realigning active site residues and relieving the steric blockage at the entrance of the catalytic cleft.
CDK (e.g., CDK2) activation requires association with cyclins (e.g., CCNE1; 123837) and phosphorylation by CAK (CCNH; 601953), and leads to cell proliferation. Inhibition of cellular proliferation occurs upon association of CDK inhibitor (e.g., CDKN1B; 600778) with a cyclin-CDK complex. Sheaff et al. (1997) showed that expression of CCNE1-CDK2 at physiologic levels of ATP results in phosphorylation of CDKN1B at thr187, leading to elimination of CDKN1B from the cell and progression of the cell cycle from G1 to S phase. At low ATP levels, the inhibitory functions of CDKN1B are enhanced, thereby arresting cell proliferation.
Apoptosis of human endothelial cells after growth factor deprivation is associated with rapid and dramatic upregulation of cyclin A-associated CDK2 activity. Levkau et al. (1998) showed that in apoptotic cells the carboxyl-termini of the CDK inhibitors CDKN1A (116899) and CDKN1B are truncated by specific cleavage. The enzyme involved in this cleavage is CASP3 (600636) and/or a CASP3-like caspase. After cleavage, CDKN1A loses its nuclear localization sequence and exits the nucleus. Cleavage of CDKN1A and CDKN1B resulted in a substantial reduction in their association with nuclear cyclin-CDK2 complexes, leading to a dramatic induction of CDK2 activity. Dominant-negative CDK2, as well as a mutant CDKN1A resistant to caspase cleavage, partially suppressed apoptosis. These data suggested that CDK2 activation, through caspase-mediated cleavage of CDK inhibitors, may be instrumental in the execution of apoptosis following caspase activation.
Shiffman et al. (1996) described the cloning of an approximately 2.4-kb genomic DNA fragment from the upstream region of the CDK2 gene. This fragment was found to contain 5 transcription initiation sites within a 72-bp stretch. A 200-bp subfragment that confers 70% of maximal basal promoter activity was shown to contain 2 synergistically acting Sp1 sites. The intron-exon boundaries of 7 exons in this gene were also identified.
By fluorescence in situ hybridization, Demetrick et al. (1994) mapped the CDK2 gene to 12q13, the same region to which the CDK4 gene (123829) maps.
Hinchcliffe et al. (1999) developed a Xenopus egg extract arrested in S phase that supported repeated assembly of daughter centrosomes. Multiple rounds of centrosome reproduction were blocked by selective inactivation of CDK2-cyclin E (123837) and were restored by addition of purified CDK2-cyclin E. Confocal microscopy revealed that cyclin E was localized at the centrosome. The authors concluded that CDK2-cyclin E activity is required for centrosome duplication during S phase and that these results suggested a mechanism that could coordinate centrosome reproduction with cycles of DNA synthesis and mitosis.
Inhibition of CDK2, a positive regulator of eukaryotic cell cycle progression, may represent a therapeutic strategy for prevention of chemotherapy-induced alopecia by arresting the cell cycle and reducing the sensitivity of the epithelium to many cell cycle-active antitumor agents. Davis et al. (2001) developed potent small-molecule inhibitors of CDK2 using structure-based methods. Topical application of these compounds in a neonatal rat model of chemotherapy-induced alopecia reduced hair loss at the site of application in 33 to 50% of the animals. Thus, Davis et al. (2001) concluded that inhibition of CDK2 represents a potentially useful approach for the prevention of chemotherapy-induced alopecia in cancer patients.
Falck et al. (2002) demonstrated that experimental blockade of either the NBS1 (602667)-MRE11 (600814) function or the CHK2 (604373)-triggered events leads to a partial radioresistant DNA synthesis phenotype in human cells. In contrast, concomitant interference with NBS1-MRE11 and the CHK2-CDC25A (116947)-CDK2 pathways entirely abolishes inhibition of DNA synthesis induced by ionizing radiation, resulting in complete RDS analogous to that caused by defective ATM (208900). In addition, CDK2-dependent loading of CDC45 (603465) onto replication origins, a prerequisite for recruitment of DNA polymerase, was prevented upon irradiation of normal or NBS1/MRE11-defective cells but not cells with defective ATM. Falck et al. (2002) concluded that in response to ionizing radiation, phosphorylation of NBS1 and CHK2 by ATM triggers 2 parallel branches of the DNA damage-dependent S-phase checkpoint that cooperate by inhibiting distinct steps of DNA replication.
Ada Hamosh - updated : 3/28/2002Paul J. Converse - updated : 4/18/2001Ada Hamosh - updated : 1/10/2001Ada Hamosh - updated : 2/15/1999Stylianos E. Antonarakis - updated : 1/21/1999Victor A. McKusick - updated : 1/20/1998Jon B. Obray - updated : 7/13/1996Moyra Smith - updated : 4/15/1996
Victor A. McKusick : 8/21/1991
carol : 3/29/2002cwells : 3/29/2002terry : 3/28/2002terry : 11/15/2001mgross : 4/18/2001mgross : 1/10/2001terry : 1/10/2001alopez : 2/15/1999carol : 1/21/1999mark : 1/22/1998terry : 1/20/1998carol : 7/13/1996carol : 4/19/1996carol : 4/15/1996carol : 4/29/1994carol : 6/28/1993supermim : 3/16/1992carol : 3/2/1992carol : 2/13/1992carol : 11/4/1991
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