Disease relevance of Cdk2

• Indeed, mice without Cdk2 are normal except for their complete sterility: unexpectedly, Cdk2 is crucial for the first meiotic division of male and female germ cells [1].
• Cell cycle control with minimal participation of Cdk2 in a murine fibrosarcoma clone cultured in protein-free medium [2].
• Finally, ablation of Cdk2 in p27(Kip1) null mice does not suppress their phenotypic defects, including development of pituitary tumors [3].
• Histone H1 phosphorylation by Cdk2 selectively modulates mouse mammary tumor virus transcription through chromatin remodeling [4].
• To elucidate the molecular mechanisms of the effects of Rh2, we have examined the Cyclin-dependent kinase-2 (Cdk2) activity in G1 arrested B16 melanoma cells and in S phase-arrested Meth-A sarcoma cells, that have been treated with Rh2 [5].

High impact information on Cdk2

• Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice [6].
• Embryonic fibroblasts lacking CDK2 proliferate normally and become immortal after continuous passage in culture [6].
• But CDK2 is essential for completion of prophase I during meiotic cell division in male and female germ cells, an unforeseen role for this cell cycle kinase [6].
• Inhibition of Cdk2 prevents centrosome reduplication and destabilizes mMps1p, causing its subsequent loss from centrosomes, suggesting that Cdk2 promotes mMps1p's centrosome duplication function by regulating its stability during S phase [7].
• Thus, mMps1p, an in vitro Cdk2 substrate, regulates centrosome duplication jointly with Cdk2 [7].

Chemical compound and disease context of Cdk2

• RESULTS: Inhibiting CDK2 activity resulted in a marked decrease in glomerular DNA synthesis [5-bromo-2'-deoxyridine (BrdU) staining] in Roscovitine-treated animals at day 5 of nephritis (P < 0.05 versus control) [8].
• METHODS: To determine if decreasing podocyte proliferation improves renal function, CDK2 activity was reduced with the purine analogue roscovitine in mice with antibody-induced experimental glomerulonephritis [8].

Biological context of Cdk2

• Furthermore, increased nuclear p21 levels and reduced expression of Cdc25A phosphatase coincided with decreases in Cdk2 activation and hepatocyte progression into S-phase [9].
• Together, these findings demonstrate a novel mechanism underlying the DNA damage-induced G(1) arrest of hematopoietic cells, that is, inhibition of Cdk2 phosphorylation and activation [10].
• Notably, the PI 3-kinase inhibitor, LY294002, completely blocked cytokine-induced Cdk2 activation and cell growth in irradiated 32D cells but not in nonirradiated cells [10].
• By contrast, ectopic expression of the Cdk2/Cdk4 interaction-deficient Delta177-191 mutant promotes differentiation and induces gene expression as effectively as wild-type C/EBPalpha [11].
• Thus, the integrity of the transactivation and DNA binding domains, but not of the Cdk2/Cdk4 interaction region, is necessary for C/EBPalpha-induced differentiation [11].

Anatomical context of Cdk2

• Our data suggest that the differentiation-specific cell cycle block in 3T3-L1 cells is resistant to high levels of c-Myc, inactivation of pocket proteins, upregulation of cyclin A levels, and Cdk2 activation, but can be abolished by a function of LTAg that is independent of binding to pocket proteins [12].
• Infection also resulted in a decrease in Cdk2 activity in both cell lines [13].
• Cdk2 was highly expressed in all spermatocytes [14].
• In p27-/- and p21-/- T cells, the pattern of protein expression was preserved, but Cdk2 activity was increased [15].
• p57(Kip2) stabilizes the MyoD protein by inhibiting cyclin E-Cdk2 kinase activity in growing myoblasts [16].

Associations of Cdk2 with chemical compounds

• These results suggest that p27Kip1 CKI is a critical target in the initial response of cancer cells to androgen depletion and plays a key role in Cdk2 inactivation through association with the kinase complex, leading to cell cycle arrest [17].
• The administration of ASA to DAB treated animals induced Cdk2 (29%) [18].
• Furthermore, CTalpha expression is decreased in cells overexpressing a dominant-negative form of CDK2 and in cells treated with the CDK2 kinase inhibitors roscovitine and olomoucine [19].
• In addition, the NH2 domain of p57(Kip2) necessary for inhibition of cyclin E-Cdk2 activity was sufficient to inhibit MyoD phosphorylation and to stabilize it, leading to its accumulation in proliferative myoblasts [16].
• Levels of the closely related Cdk2 inhibitor, p21(Cip1), are unaffected by cicaprost [20].

Physical interactions of Cdk2

• Immunoprecipitates of cyclin E1 complexes from Cdk2(-/-) spleen extracts displayed no activity toward histone H1 [21].
• Accordingly, co-expression with cyclin A/Cdk2 in cells did not inhibit the DNA binding and transcriptional activities of CDP/Cux p110 [22].
• Cyclin D1/cdk2 kinase is present in a G1 phase-specific protein complex Yi1 that binds to the mouse thymidine kinase gene promoter [23].
• Moreover, these mutants of p27Kip1 are also impaired in disrupting the interaction between cyclin/cdk2 and the repressor complexes of E2Fs [24].
• By gel mobility shift, E2F1 was found in P2 c-myc band shift complexes along with the cyclin-dependent kinase 2 [25].

Regulatory relationships of Cdk2

• These results suggest the existence of a feedback loop where Cdk2 controls its own activity through regulation of cyclin E1 transcription [26].
• A dominant-negative Cdk2 mutant arrested cells at the G(1) phase transition and induced hypophosphorylation of MyoD [16].
• Up-regulation of c-myc induces the gene expression of the murine homologues of p34cdc2 and cyclin-dependent kinase-2 in T lymphocytes [27].
• The truncated cyclin A2 binds to and activates the cyclin-dependent kinase 2 (CDK2) [28].
• Antisense Cdk2 kinase oligodeoxynucleotide inhibits ICAM-1 expression in murine cardiac allograft arteriopathy [29].
• Substitution of both copies of Cdk1 by Cdk2 led to early embryonic lethality, even though Cdk2 was expressed from the Cdk1 locus [30].

Other interactions of Cdk2

• Changes in rates of cell division, cell cycle structure and the establishment of cell cycle-regulated Cdk2 activity can therefore be explained by activation of the E2F-pRb pathway [26].
• Yi1 contains cyclin D1/cdk2 kinase as shown by using specific antibodies to cyclins, cdks and the Yi1 DNA-binding protein in gel retardation, western blotting, and immunoprecipitation assays [23].
• Mouse knockouts of Cdk2 and Cdk4 have demonstrated that, individually, these genes are not essential for viability [31].
• Cytokine treatment of irradiated cells induced Cdk2 phosphorylation and activation, and cells entered into S phase despite sustained high-level expression of p21 and p27 [10].
• Our in vivo results provide strong evidence that Cdc2 may compensate the loss of Cdk2 function [32].

Analytical, diagnostic and therapeutic context of Cdk2

• In contrast, B cell entry into S phase was accompanied by an induction in the expression of cellular Cdk2 as judged by immunoblotting of B cell lysates with anti-Cdk2 antibodies [33].
• Importantly, the down-regulation of p21(CIP1) and p27(KIP1) was completely blocked by three distinct proteasome inhibitors, demonstrating that integrin ligation induced proteasomal degradation of these Cdk2 inhibitors [34].
• Analysis of one of the cyclin-dependent kinases, Cdk2 protein, by Western blot revealed that Cdk2 levels were decreased, in the presence of leflunomide, 48 hr after stimulation [35].
• Thus, Rh2 has a G1 phase-specific suppressive effect on the Cdk2 activity, supporting further evaluation of Rh2 and its related compounds in cancer chemoprevention studies [5].
• Downregulation of endothelin expression in allograft coronary arteries after gene therapy targeting Cdk2 kinase [36].

References