CDK4 constitutes the catalytic subunit of a heterodimeric Ser/Thr protein kinase which is involved in controlling progression through the G1 phase of the cell cycle. The activating partner of CDK4 (the regulatory subunit) is one of the D-type cyclins: CCND1, CCND2 or CCND3. Once activated, the CDK4-cyclin D complex phosphorylates members of the retinoblastoma protein family (pRb, p107, p130). The activity of CDK4 is inhibited by the p16 (INK4A) protein, which interferes with the cyclin D-binding region.
Germinal: germ-line mutations in the CDK4 gene have so far only been found in families with inherited malignant melanoma (familial cutaneous malignant melanoma 3 or CMM3) and multiple atypical nevi. There are six such families reported. The mutations affect the Arg encoded by codon 24, changing it either to Cys (two families) or to His (four families).
Somatic: amplification of the chromosomal region that includes CDK4 and CDK4 overexpression is commonly seen in gliomas and several subgroups of sarcomas (in particular liposarcoma, alveolar rhabdomyosarcoma and osteosarcoma), and may also occur in other tumors such as malignant melanomas (cases with wild-type BRAF and NRAS genes), and carcinomas of the breast, colon, lung, ovary and oral cavity. Point mutations have only rarely been observed and are of unknown biological significance.
CDK4 inhibitors are in development. This is notably the case of PD 0332991, a selective cyclin D kinase 4/6 inhibitor.
References (open access):
Main roads to melanoma. Palmieri G, Capone M, Ascierto ML, Gentilcore G, Stroncek DF, Casula M, Sini MC, Palla M, Mozzillo N, Ascierto PA. J Transl Med. 2009 Oct 14;7:86.
Clinical and biological significance of CDK4 amplification in well-differentiated and dedifferentiated liposarcomas. Italiano A, Bianchini L, Gjernes E, Keslair F, Ranchere-Vince D, Dumollard JM, Haudebourg J, Leroux A, Mainguené C, Terrier P, Chibon F, Coindre JM, Pedeutour F. Clin Cancer Res. 2009 Sep 15;15(18):5696-703.