CDK4 (cyclin-dependent kinase 4)

Identity

Other names	CMM3
	MGC14458
	PSK-J3
HGNC	CDK4
Location	12q14
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.

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

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

External links

	Nomenclature
HGNC	CDK4   1773
Entrez_Gene	CDK4  1019  cyclin-dependent kinase 4
	Cards
Atlas	CDK4ID238ch12q14
GeneCards	CDK4
Ensembl	CDK4 [Search_View]   ENSG00000135446 [Gene_View]
Genatlas	CDK4
GeneLynx	CDK4
eGenome	CDK4
euGene	1019
	Genomic and cartography
GoldenPath	CDK4  -  12q14   chr12:56428270-56432431 -  12q13   [Description]    (hg18-Mar_2006)
Ensembl	CDK4 - 12q13 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	CDK4
	Gene and transcription
Genbank	AK297901 [ ENTREZ ]
Genbank	AK310724 [ ENTREZ ]
Genbank	AK313701 [ ENTREZ ]
Genbank	BC003644 [ ENTREZ ]
Genbank	BC005864 [ ENTREZ ]
RefSeq	NM_000075 [ SRS ]    NM_000075 [ ENTREZ ]
RefSeq	AC_000055 [ SRS ]    AC_000055 [ ENTREZ ]
RefSeq	AC_000144 [ SRS ]    AC_000144 [ ENTREZ ]
RefSeq	NC_000012 [ SRS ]    NC_000012 [ ENTREZ ]
RefSeq	NG_007484 [ SRS ]    NG_007484 [ ENTREZ ]
RefSeq	NT_029419 [ SRS ]    NT_029419 [ ENTREZ ]
RefSeq	NW_001838060 [ SRS ]    NW_001838060 [ ENTREZ ]
RefSeq	NW_925395 [ SRS ]    NW_925395 [ ENTREZ ]
AceView	CDK4 AceView - NCBI
Unigene	Hs.95577 [ SRS ]    Hs.95577 [ NCBI ]     HS95577 [ spliceNest ]
Fast-db	9527 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P11802 [ SRS]    P11802 [ EXPASY ]     P11802 [ INTERPRO ]     P11802 [ UNIPROT ]
Prosite	PS00107 PROTEIN_KINASE_ATP [ SRS ]    PS00107 PROTEIN_KINASE_ATP [ Expasy ]
Prosite	PS50011 PROTEIN_KINASE_DOM [ SRS ]    PS50011 PROTEIN_KINASE_DOM [ Expasy ]
Prosite	PS00108 PROTEIN_KINASE_ST [ SRS ]    PS00108 PROTEIN_KINASE_ST [ Expasy ]
Interpro	IPR000719 Prot_kinase_core [ SRS ]    IPR000719 Prot_kinase_core [ EBI ]
Interpro	IPR017441 Protein_kinase_ATP_bd_CS [ SRS ]    IPR017441 Protein_kinase_ATP_bd_CS [ EBI ]
Interpro	IPR017442 Se/Thr_pkinase-rel [ SRS ]    IPR017442 Se/Thr_pkinase-rel [ EBI ]
Interpro	IPR008271 Ser_thr_pkin_AS [ SRS ]    IPR008271 Ser_thr_pkin_AS [ EBI ]
Interpro	IPR002290 Ser_thr_pkinase [ SRS ]    IPR002290 Ser_thr_pkinase [ EBI ]
CluSTr	P11802
Pfam	PF00069 Pkinase [ SRS ]    PF00069 Pkinase [ Sanger ]    pfam00069 [ NCBI-CDD ]
Smart	SM00220 S_TKc [EMBL]
Prodom	PD000001 Prot_kinase[INRA-Toulouse]
Prodom	P11802 CDK4_HUMAN [ Domain structure ]   P11802 CDK4_HUMAN  [ sequences sharing at least 1 domain ]
Blocks	P11802
PDB	1LD2 [ SRS ]    1LD2 [ PdbSum ],   1LD2 [ IMB ]   1LD2 [ RSDB ]
HPRD	00447
	Protein Interaction databases
DIP	P11802
IntAct	P11802
	Polymorphism : SNP, mutations, diseases
OMIM	123829;609048    [ map ]
GENECLINICS	123829;609048
SNP	CDK4 [dbSNP-NCBI]
SNP	NM_000075 [SNP-NCI]
SNP	CDK4 [GeneSNPs - Utah]  CDK4] [HGBASE - SRS]
HAPMAP	CDK4 [HAPMAP]
COSMIC	CDK4 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	CDK4
	General knowledge
Family Browser	CDK4 [UCSC Family Browser]
SOURCE	NM_000075
SMD	Hs.95577
SAGE	Hs.95577
Enzyme	2.7.11.22 [ Enzyme-Expasy ]   2.7.11.22 [ Enzyme-SRS ]   2.7.11.22 [ IntEnz-EBI ]   2.7.11.22 [ BRENDA ]   2.7.11.22 [ KEGG ]   2.7.11.22 [ WIT ]
GO	G1/S transition of mitotic cell cycle [Amigo]  G1/S transition of mitotic cell cycle
GO	nucleotide binding [Amigo]  nucleotide binding
GO	cyclin-dependent protein kinase holoenzyme complex [Amigo]  cyclin-dependent protein kinase holoenzyme complex
GO	protein kinase activity [Amigo]  protein kinase activity
GO	cyclin-dependent protein kinase activity [Amigo]  cyclin-dependent protein kinase activity
GO	protein binding [Amigo]  protein binding
GO	ATP binding [Amigo]  ATP binding
GO	nucleus [Amigo]  nucleus
GO	nucleoplasm [Amigo]  nucleoplasm
GO	cytosol [Amigo]  cytosol
GO	protein amino acid phosphorylation [Amigo]  protein amino acid phosphorylation
GO	cell cycle [Amigo]  cell cycle
GO	regulation of gene expression [Amigo]  regulation of gene expression
GO	transferase activity [Amigo]  transferase activity
GO	positive regulation of fibroblast proliferation [Amigo]  positive regulation of fibroblast proliferation
GO	cell division [Amigo]  cell division
BIOCARTA	Influence of Ras and Rho proteins on G1 to S Transition    [Genes]
BIOCARTA	Cyclins and Cell Cycle Regulation    [Genes]
BIOCARTA	Cell Cycle: G1/S Check Point    [Genes]
BIOCARTA	p53 Signaling Pathway    [Genes]
BIOCARTA	RB Tumor Suppressor/Checkpoint Signaling in response to DNA damage    [Genes]
KEGG	Cell cycle
KEGG	Tight junction
KEGG	T cell receptor signaling pathway
PubGene	CDK4
TreeFam	CDK4
CTD	1019 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	CDK4 Related clones (RZPD - Berlin)
	PubMed
PubMed	146 Pubmed reference(s) in LocusLink

Bibliography

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

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

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

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, BˆŠnard J, Bressac-de Paillerets B

Human molecular genetics. 1998 ; 7 (2) : 209-216.

PMID 9425228

Distinct sets of genetic alterations in melanoma.

Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Brˆcker EB, LeBoit PE, Pinkel D, Bastian BC

The New England journal of medicine. 2005 ; 353 (20) : 2135-2147.

PMID 16291983

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

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Contributor(s)

Written	01-2007	Anders Molven

Citation

This paper should be referenced as such :

Molven A . CDK4 (cyclin-dependent kinase 4). Atlas Genet Cytogenet Oncol Haematol. January 2007 . URL : http://AtlasGeneticsOncology.org/Genes/CDK4ID238ch12q14.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:12:53 2008