Disease relevance of CDK3

• Retinoic acid-mediated G1 arrest is associated with induction of p27(Kip1) and inhibition of cyclin-dependent kinase 3 in human lung squamous carcinoma CH27 cells [1].
• Among them are binding by the retinoblastoma gene product (pRb), activation by cdk3, and S-phase-dependent down-regulation of DNA-binding capacity by cyclin A-dependent kinase [2].

High impact information on CDK3

• Cyclin C/cdk3 promotes Rb-dependent G0 exit [3].
• These data reveal that Cdk3, in addition to Cdc2 and Cdk2, executes a distinct and essential function in the mammalian cell cycle [4].
• Cdk3 bound specifically to E2F-1/DP-1 complexes in vivo, most likely through DP-1 [5].
• In contrast, little is known about CDK3, a homolog of CDK2 and cell division cycle kinase 2 (CDC2) [6].
• Herein we report the presence of a single point mutation in the CDK3 gene from several Mus musculus strains commonly used in the laboratory [6].

Biological context of CDK3

• Here we show that a novel kinase activity associated with cdk3 fluctuates throughout the cell cycle differently from the expression of cyclin D1-, E- and A-associated kinase activities [7].
• Here we report that RA mediated the dose- and time-dependent growth arrest in G1 phase, accompanied by the up-regulation of p27(Kip1) and the down-regulation of the cyclin-dependent kinase 3 (Cdk3) and p21(CIP1/Waf1) proteins [1].
• We therefore conclude that p70ik3-1 is a substrate for cdk3-mediated phosphorylation [8].
• In this report, we provide evidence for a not yet described property of CDK2 or CDK3 besides their activity in promoting proliferation: these G1-CDKs can promote apoptosis by interfering with the cell's response to survival factors [9].
• These apoptotic effects of CDK2 or CDK3 are not accompanied by alterations of proliferation parameters, such as DNA distribution, time the cells spend in each phase of the cell cycle, thymidine incorporation into DNA, or cell size analyzed during Myc-induced apoptosis [9].

Anatomical context of CDK3

• In contrast to all other studied positive G regulators, cdk3 is unable to cooperate with ras in fibroblast transformation suggesting a function of cdk3 in G1 progression that is different from cyclin D- or E-associated kinase activities [7].

Associations of CDK3 with chemical compounds

• Here, we show that neither CDK2 nor CDK3 induces susceptibility to the cytotoxic action of TNF in Rat1 cells [9].
• Early G1-phase activation of cdk3 was downregulated by treatment of cells with MG132, an inhibitor of the proteasome, and by the protein synthesis inhibitor cycloheximide [10].
• In vitro cdk3 activity was sensitive to roscovitine, a drug previously shown to inhibit cdks 1, 2, and 5, but not cdk4 or 6 [10].

Physical interactions of CDK3

• In an article published recently in Cell, Ren and Rollins investigate mechanisms controlling the G0/G1 transition in quiescent cells and identify new cyclin C/Cdk3 complexes as key regulators of cell cycle reentry in human cells [11].

Regulatory relationships of CDK3

• Differential effects of cdk2 and cdk3 on the control of pRb and E2F function during G1 exit [5].

Other interactions of CDK3

• The G1-S transition in mammalian cells has been demonstrated to require the cyclin-dependent kinases cdk2, cdk3 and cdk4/6 [7].
• These results suggest that increases in the levels of p27(Kip1) and its binding to cyclin A, as well as reduction of Cdk3 protein expression, are strong candidates for the cell cycle regulator that prevents the entry into the S phase in RA-treated CH27 cells, with prolongation of G1 phase and inhibition of DNA synthesis [1].
• We also found that in COS7 cells in which cyclin E and cdk3 were ectopically overexpressed, the phosphorylation level of Ser274 in coexpressed p70ik3-1 is upregulated [8].
• In spite of its structural similarity to cyclins, p70ik3-1 does not activate cyclin-dependent kinase 3 (cdk3)-mediated phosphorylation of pRb, histone H1, or the C-terminal domain of RNA polymerase II [8].
• Transfection with dominant-negative Cdk mutants demonstrated that only a Cdk2 mutant increased Cdc25A protein levels; Cdk1 and Cdk3 mutants had no effect [12].

References