Cyclin-dependent kinase 4

Cyclin-dependent kinase 4 also known as cell division protein kinase 4 is an enzyme that in humans is encoded by the CDK4 gene. CDK4 is a member of the cyclin-dependent kinase family.

Function

The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This protein is highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalytic subunit of the protein kinase complex that is important for cell cycle G1 phase progression. The activity of this kinase is restricted to the G1-S phase, which is controlled by the regulatory subunits D-type cyclins and CDK inhibitor p16^INK4a. This kinase was shown to be responsible for the phosphorylation of retinoblastoma gene product (Rb). Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G1/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G1phase. Hypophosphorylates RB1 in early G1 phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex.

Clinical significance

Mutations in this gene as well as in its related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associated with tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have been reported.

It is regulated by Cyclin D.

Inhibitors

Palbociclib is US FDA approved (Feb 2015) for estrogen receptor-positive advanced breast cancer.

See also CDK inhibitor for inhibitors of various CDKs.

Interactions

Cyclin-dependent kinase 4 has been shown to interact with:

• CDC37,
• CDKN1B,
• CDKN2B,
• CDKN2C,
• CEBPA,
• CCND1,
• CCND3,
• DBNL,
• MyoD,
• P16,
• PCNA, and
• SERTAD1.

Overview of signal transduction pathways involved in apoptosis.

External links

• Cyclin-Dependent Kinase 4 at the US National Library of Medicine Medical Subject Headings (MeSH)
• CDK4 human gene location in the UCSC Genome Browser.
• CDK4 human gene details in the UCSC Genome Browser.