| Written | 2007-01 | Anders Molven |
| Section for Pathology, The Gade Institute, Haukeland University Hospital, N-5021 Bergen, Norway |
| Identity |
| Alias_symbol (synonym) | PSK-J3 |
| Other alias | CMM3 |
| MGC14458 | |
| HGNC (Hugo) | CDK4 |
| LocusID (NCBI) | 1019 |
| Atlas_Id | 238 |
| Location | 12q14.1 [Link to chromosome band 12q14] |
| Location_base_pair | Starts at 57747727 and ends at 57752447 bp from pter ( according to hg19-Feb_2009) [Mapping CDK4.png] |
| Local_order | Telomeric to the OS9 (amplified in osteosarcoma 9), CENTG1 (centaurin, gamma 1) and TSPAN31 (tetraspanin 31, SAS) genes. Centromeric to the MARCH9 (membrane-associated ring finger (C3HC4) 9), CYP27B1 (cytochrome P450, family 27, subfamily B, polypeptide 1) and METTL1 (methyltransferase like 1) genes. These seven genes are clustered within a genomic region of about 75 kb. |
| Fusion genes (updated 2016) | CCND1 (11q13.3) / CDK4 (12q14.1) | CDK4 (12q14.1) / ARV1 (1q42.2) | CDK4 (12q14.1) / RPL4 (15q22.31) |
| CDK4 (12q14.1) / UBA1 (Xp11.23) |
| DNA/RNA |
 | |
| Genomic organization of the CDK4 gene on chromosome 12. | |
| Description | CDK4 is a relatively compact gene that spans 4.16 kb of genomic DNA on the long arm of chromosome 12, in the telomere-to-centromere orientation. The gene consists of eight exons of which the first exon is non-coding. The start codon is located in the beginning of exon 2 and the stop codon in the beginning of exon 8. |
| Transcription | The CDK4 mRNA is 1.44 kb. In the Ensembl database, also a shorter, alternatively spliced transcript (Q96BE9_HUMAN) is listed, but there is no biological evidence for a function of this transcript or the polypeptide it may encode. |
| Pseudogene | The Ensembl database lists OTTHUMG00000011002 (Vega gene RP11-414B7.1) on chromosome 1 as a processed pseudogene of CDK4. |
| Protein |
| Description | The open reading frame encodes a 303 amino acid protein with an estimated molecular weight of 33.7 kDa. CDK4 is member of the Ser-Thr protein kinase family and its catalytic domain extends from amino acid 6 to 295. |
| Expression | CDK4 is expressed in a variety of normal cells and tissues as well as in cancer cells. The protein is often overexpressed in human tumors (e.g. malignant melanoma, glioma, sarcoma and carcinomas of the breast, colon, lung, ovary and oral cavity). |
| Localisation | Nuclear or nuclear/cytoplasmic |
| Function | 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. |
| Homology | CDK4 belongs to the mammalian Cdk family, which includes about 20 members. The cyclin-binding domain of CDK4 has the amino acid sequence PISTVRE. The overall identity of CDK4 to CDK1 is 42%. |
| Mutations |
| Germinal | Germ-line mutations in the CDK4 gene have so far only been found in families with inherited malignant melanoma 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 is commonly seen in gliomas and several subgroups of sarcomas, and may also occur in other tumors such a malignant melanomas. Point mutations have only rarely been observed and are of unknown biological significance. |
| Implicated in |
| Note | |
| Entity | Familial cutaneous malignant melanoma 3 (CMM3) |
| Entity | Sporadic malignant melanoma |
| Note | Cases with wild-type BRAF and NRAS genes |
| Entity | Glioma |
| Disease | Anaplastic astrocytoma and glioblastoma multiforme |
| Entity | Sarcoma |
| Disease | In particular liposarcoma, alveolar rhabdomyosarcoma and osteosarcoma |
| Bibliography |
| Distinct sets of genetic alterations in melanoma. |
| Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Bröcker EB, LeBoit PE, Pinkel D, Bastian BC |
| The New England journal of medicine. 2005 ; 353 (20) : 2135-2147. |
| PMID 16291983 |
| Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. |
| Khatib ZA, Matsushime H, Valentine M, Shapiro DN, Sherr CJ, Look AT |
| Cancer research. 1993 ; 53 (22) : 5535-5541. |
| PMID 8221695 |
| Mammalian cyclin-dependent kinases. |
| Malumbres M, Barbacid M |
| Trends in biochemical sciences. 2005 ; 30 (11) : 630-641. |
| PMID 16236519 |
| A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutation. |
| Molven A, Grimstvedt MB, Steine SJ, Harland M, Avril MF, Hayward NK, Akslen LA |
| Genes, chromosomes & cancer. 2005 ; 44 (1) : 10-18. |
| PMID 15880589 |
| Amplification of multiple genes from chromosomal region 12q13-14 in human malignant gliomas: preliminary mapping of the amplicons shows preferential involvement of CDK4, SAS, and MDM2. |
| Reifenberger G, Reifenberger J, Ichimura K, Meltzer PS, Collins VP |
| Cancer research. 1994 ; 54 (16) : 4299-4303. |
| PMID 8044775 |
| Molecular changes during the genesis of human gliomas. |
| Sehgal A |
| Seminars in surgical oncology. 1998 ; 14 (1) : 3-12. |
| PMID 9407626 |
| Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group. |
| Soufir N, Avril MF, Chompret A, Demenais F, Bombled J, Spatz A, Stoppa-Lyonnet D, Bénard J, Bressac-de Paillerets B |
| Human molecular genetics. 1998 ; 7 (2) : 209-216. |
| PMID 9425228 |
| Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma. |
| Zuo L, Weger J, Yang Q, Goldstein AM, Tucker MA, Walker GJ, Hayward N, Dracopoli NC |
| Nature genetics. 1996 ; 12 (1) : 97-99. |
| PMID 8528263 |
| Citation |
| This paper should be referenced as such : |
| Molven, A |
| CDK4 (cyclin-dependent kinase 4) |
| Atlas Genet Cytogenet Oncol Haematol. 2007;11(2):117-118. |
| Free journal version : [ pdf ] [ DOI ] |
| On line version : http://AtlasGeneticsOncology.org/Genes/CDK4ID238ch12q14.html |
| Other Leukemias implicated (Data extracted from papers in the Atlas) [ 6 ] |
| Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 15 ] |
| Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ] |
| Familial melanoma |
| External links |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Fri Jun 30 11:03:09 CEST 2017 |
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