Disease relevance of Cdk4

• To test this hypothesis, we used the RNA alphavirus Sindbis to express three known cyclin dependent kinase inhibitors (CKIs), p16(ink4), p21(waf/cip), and p27(kip1), and dominant negative mutant forms of four known G1 cyclin dependent kinases (CDKs), Cdk2, Cdk3, Cdk4, and Cdk6, in primary cultured rat superior cervical ganglion sympathetic neurons [1].
• Levels of Cdk4 mRNA were increased significantly in HCC compared to precancerous and chronic hepatitis livers [2].
• Inhibition of Cdk4 activity during this ischemia/reperfusion is highly neuroprotective [3].
• Coinfection of recombinant adenoviruses expressing D1NLS and CDK4 induced Rb phosphorylation and CDK2 kinase activity [4].

High impact information on Cdk4

• Here we show that tyrosine phosphorylation of Cdk4 is required for this arrest [5].
• In rat fibroblast, Cdk4 is tyrosine-phosphorylated during G1 progression, and its dephosphorylation is required for S phase [5].
• The cyclin-dependent kinase 4 (CDK4) regulates progression through the G1 phase of the cell cycle [6].
• The activity of CDK4 is controlled by the opposing effects of the D-type cyclin, an activating subunit, and p16INK4, an inhibitory subunit [6].
• Ectopic expression of p16INK4 blocked entry into S phase of the cell cycle induced by oncogenic Ha-Ras, and this block was relieved by coexpression of a catalytically inactive CDK4 mutant [6].

Biological context of Cdk4

• When stimulated with serum, NRK cells rely on cyclin-dependent kinase 4 (Cdk4) for their S phase entry [7].
• Progression through the early G(1) phase of the cell cycle requires mitogenic stimulation, which ultimately leads to the activation of cyclin-dependent kinases 4 and 6 (Cdk4/6) [8].
• This process involves downregulation of cyclin D1 and Cdk4 at the level of protein expression, whereas the mRNA levels remain relatively unchanged [9].
• The authors determined whether nontransformed rat intestinal epithelial cells (IECs) underwent reversible cell cycle arrest by contact inhibition, and determined whether increases in the relative amount of p21 associated with cyclin D/Cdk4 protein complexes were associated with cell growth arrest [9].
• Cdk4/cyclin D1 levels and phosphorylation of its substrate retinoblastoma protein (pRb) increase after stroke [10].

Anatomical context of Cdk4

• In mink lung epithelial cells, TGF-beta 1 inhibits Cdk4 expression [11].
• These results indicate that cyclin D1 may be involved in the regeneration of hepatocytes rather than hepatocarcinogenesis, while Cdk4 but not Cdk6 may play an important role in the development of HCC [2].
• Our findings indicate that estrogen and its receptors enhance Cdk4/6 activities through the induction of D-type cyclins, leading to the growth promotion of osteoblasts [12].
• Although the cell cycle of the rat fibroblast cell line, 3Y1, was arrested in quiescence by contact inhibition, the Cdk4 bound to its regulatory subunit, cyclin D1 or D3 [13].
• Because treatment of cells with anti-calmodulin drugs decreases the nuclear accumulation of p21(Cip1), we hypothesize that calmodulin interaction with p21(Cip1) is important for p21(Cip1), and in consequence for cyclin D-Cdk4, translocation into the cell nucleus [14].

Associations of Cdk4 with chemical compounds

• Cyclin D1, Cdk4, and p21 protein complex formation was analyzed by immunoprecipitating the complexes from cell lysates with an antibody to one of the constituents, followed by SDS polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis of the precipitated complexes using antibodies to the other proteins [9].
• Expression of angiotensin type II receptor downregulates Cdk4 synthesis and inhibits cell-cycle progression [15].
• It is now demonstrated that the modification of pyrido[2,3-d]pyrimidin-7-ones to include a 2-aminopyridine side chain at the C2-position provides inhibitors with exquisite selectivity for Cdk4/6 in vitro [16].
• Association of cyclin-dependent kinase-4 and cyclin D1 in neonatal beta cells after mitogenic stimulation by lysophosphatidic acid [17].
• Our results suggest that CDK4 and cyclin D1 are essential for KA-induced neuronal apoptosis in vivo [18].

Regulatory relationships of Cdk4

• Thus, ET-1 induced cyclin D1 expression and stimulated CDK4 activity and cell cycle progression via the A-type receptor in rat mesangial cells [19].

Other interactions of Cdk4

• ATRA did not influence the expressions of Cip/Kip family Cdk inhibitors or those of cyclins D1 and D2, whereas it strongly inhibited the expressions of cyclins D3 and E, Cdk4, Cdk6, and Cdk2 [20].
• In addition, we show that expression of dominant negative forms of Cdk4 or Cdk6, but not Cdk2 or Cdk3, protects NGF-deprived sympathetic neurons from death [1].
• The levels of cyclin D1 increased 5.8-fold and Cdk4 increased by 4.4-fold by 24 hours after reseeding the day 9 density-arrested cultures, coincident with the increase in DNA synthesis [9].
• Recovery of Cdk4-dependent kinase activity occurred by 4 hours after release from growth arrest, coincident with decreased binding of p21 to the complex [9].
• Cdk-activating kinase did not rescue Cdk4/6 activity [8].

Analytical, diagnostic and therapeutic context of Cdk4

• Cyclin D1, Cdk4, and p21 mRNA and protein levels were determined by standard Northern and Western blot analyses, respectively [9].
• Although cyclin D1/Cdk4 complexes were more abundant in the cytoplasmic fraction after partial hepatectomy, kinase activity was detected primarily in the nuclear fraction [21].
• Expression of p16ink4a, cyclin D1, Cdk4, and Rb in relation to that of proliferating cell nuclear antigen was characterized in esophagi by immunohistochemistry at 0, 24, and 48 h, and 1, 3, 7, 10, and 14 weeks after NMBA treatment [22].
• The cell cycle of mesangial cells was evaluated by measurement of [3H]-thymidine incorporation, flow cytometry, and cyclin-dependent kinase 4 kinase assay [23].
• Expression of cyclins and cyclin-dependent kinase 4 was evaluated by Western and Northern blotting [24].

References