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CDK4 (cyclin-dependent kinase 4)

Identity

Other namesCMM3
MGC14458
PSK-J3
HGNC (Hugo) CDK4
LocusID (NCBI) 1019
Location 12q14.1
Location_base_pair Starts at 58141510 and ends at 58146230 bp from pter ( according to hg19-Feb_2009)  [Mapping]
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
  

Other Leukemias implicated (Data extracted from papers in the Atlas)

Leukemias 11q23ChildAMLID1615 11q23ID1030 11q23secondLeukID1131 t1119ELLID1029

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors AmeloblastomID5945 MedulloblastomaID5065 rhab5004 rhabID5004 blad5001
bladID5001

External links

Nomenclature
HGNC (Hugo)CDK4   1773
Cards
AtlasCDK4ID238ch12q14
Entrez_Gene (NCBI)CDK4  1019  cyclin-dependent kinase 4
GeneCards (Weizmann)CDK4
Ensembl (Hinxton)ENSG00000135446 [Gene_View]  chr12:58141510-58146230 [Contig_View]  CDK4 [Vega]
ICGC DataPortalENSG00000135446
cBioPortalCDK4
AceView (NCBI)CDK4
Genatlas (Paris)CDK4
WikiGenes1019
SOURCE (Princeton)NM_000075 NM_052984
Genomic and cartography
GoldenPath (UCSC)CDK4  -  12q14.1   chr12:58141510-58146230 -  12q13   [Description]    (hg19-Feb_2009)
EnsemblCDK4 - 12q13 [CytoView]
Mapping of homologs : NCBICDK4 [Mapview]
OMIM123829   609048   
Gene and transcription
Genbank (Entrez)AK297901 AK310724 AK313701 BC003644 BC005864
RefSeq transcript (Entrez)NM_000075 NM_052984
RefSeq genomic (Entrez)AC_000144 NC_000012 NC_018923 NG_007484 NT_029419 NW_001838060 NW_004929384
Consensus coding sequences : CCDS (NCBI)CDK4
Cluster EST : UnigeneHs.95577 [ NCBI ]
CGAP (NCI)Hs.95577
Alternative Splicing : Fast-db (Paris)GSHG0007577
Alternative Splicing GalleryENSG00000135446
Gene ExpressionCDK4 [ NCBI-GEO ]     CDK4 [ SEEK ]   CDK4 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP11802 (Uniprot)
NextProtP11802  [Medical]
With graphics : InterProP11802
Splice isoforms : SwissVarP11802 (Swissvar)
Catalytic activity : Enzyme2.7.11.22 [ Enzyme-Expasy ]   2.7.11.222.7.11.22 [ IntEnz-EBI ]   2.7.11.22 [ BRENDA ]   2.7.11.22 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)Kinase-like_dom [organisation]   Prot_kinase_dom [organisation]   Protein_kinase_ATP_BS [organisation]   Ser/Thr_dual-sp_kinase_dom [organisation]   Ser/Thr_kinase_AS [organisation]  
Related proteins : CluSTrP11802
Domain families : Pfam (Sanger)Pkinase (PF00069)   
Domain families : Pfam (NCBI)pfam00069   
Domain families : Smart (EMBL)S_TKc (SM00220)  
DMDM Disease mutations1019
Blocks (Seattle)P11802
PDB (SRS)1LD2    2W96    2W99    2W9F    2W9Z    3G33   
PDB (PDBSum)1LD2    2W96    2W99    2W9F    2W9Z    3G33   
PDB (IMB)1LD2    2W96    2W99    2W9F    2W9Z    3G33   
PDB (RSDB)1LD2    2W96    2W99    2W9F    2W9Z    3G33   
Human Protein AtlasENSG00000135446 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP11802
HPRD00447
IPIIPI00007811   IPI01011274   IPI00059926   IPI01022897   IPI01021473   IPI01021663   IPI01021221   IPI01021327   IPI01022046   IPI01022249   IPI01021794   IPI01021938   
Protein Interaction databases
DIP (DOE-UCLA)P11802
IntAct (EBI)P11802
FunCoupENSG00000135446
BioGRIDCDK4
InParanoidP11802
Interologous Interaction database P11802
IntegromeDBCDK4
STRING (EMBL)CDK4
Ontologies - Pathways
Ontology : AmiGOG1/S transition of mitotic cell cycle  mitotic cell cycle  cyclin-dependent protein kinase holoenzyme complex  chromatin  cyclin-dependent protein serine/threonine kinase activity  protein binding  ATP binding  nucleus  nucleoplasm  transcription factor complex  nucleolus  cytosol  cytosol  tight junction  protein phosphorylation  signal transduction  circadian rhythm  positive regulation of cell proliferation  response to toxic substance  response to lead ion  regulation of gene expression  positive regulation of G2/M transition of mitotic cell cycle  cyclin binding  organ regeneration  nuclear membrane  protein complex binding  response to testosterone  response to drug  positive regulation of apoptotic process  positive regulation of translation  positive regulation of cell size  positive regulation of fibroblast proliferation  perinuclear region of cytoplasm  cell division  response to hyperoxia  negative regulation of cell cycle arrest  
Ontology : EGO-EBIG1/S transition of mitotic cell cycle  mitotic cell cycle  cyclin-dependent protein kinase holoenzyme complex  chromatin  cyclin-dependent protein serine/threonine kinase activity  protein binding  ATP binding  nucleus  nucleoplasm  transcription factor complex  nucleolus  cytosol  cytosol  tight junction  protein phosphorylation  signal transduction  circadian rhythm  positive regulation of cell proliferation  response to toxic substance  response to lead ion  regulation of gene expression  positive regulation of G2/M transition of mitotic cell cycle  cyclin binding  organ regeneration  nuclear membrane  protein complex binding  response to testosterone  response to drug  positive regulation of apoptotic process  positive regulation of translation  positive regulation of cell size  positive regulation of fibroblast proliferation  perinuclear region of cytoplasm  cell division  response to hyperoxia  negative regulation of cell cycle arrest  
Pathways : BIOCARTARB Tumor Suppressor/Checkpoint Signaling in response to DNA damage [Genes]    p53 Signaling Pathway [Genes]    Cell Cycle: G1/S Check Point [Genes]    Estrogen-responsive protein Efp controls cell cycle and breast tumors growth [Genes]    Influence of Ras and Rho proteins on G1 to S Transition [Genes]    Cyclins and Cell Cycle Regulation [Genes]   
Pathways : KEGGCell cycle    p53 signaling pathway    PI3K-Akt signaling pathway    Tight junction    T cell receptor signaling pathway    Hepatitis B    Measles    HTLV-I infection    Pathways in cancer    Viral carcinogenesis    Pancreatic cancer    Glioma    Melanoma    Bladder cancer    Chronic myeloid leukemia    Small cell lung cancer    Non-small cell lung cancer   
Protein Interaction DatabaseCDK4
Wikipedia pathwaysCDK4
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)CDK4
snp3D : Map Gene to Disease1019
SNP (GeneSNP Utah)CDK4
SNP : HGBaseCDK4
Genetic variants : HAPMAPCDK4
Exome VariantCDK4
1000_GenomesCDK4 
ICGC programENSG00000135446 
Cancer Gene: CensusCDK4 
Somatic Mutations in Cancer : COSMICCDK4 
CONAN: Copy Number AnalysisCDK4 
Mutations and Diseases : HGMDCDK4
Mutations and Diseases : intOGenCDK4
Genomic VariantsCDK4  CDK4 [DGVbeta]
dbVarCDK4
ClinVarCDK4
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM123829    609048   
MedgenCDK4
GENETestsCDK4
Disease Genetic AssociationCDK4
Huge Navigator CDK4 [HugePedia]  CDK4 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneCDK4
Homology/Alignments : Family Browser (UCSC)CDK4
Phylogenetic Trees/Animal Genes : TreeFamCDK4
Chemical/Protein Interactions : CTD1019
Chemical/Pharm GKB GenePA102
Drug Sensitivity CDK4
Clinical trialCDK4
Cancer Resource (Charite)ENSG00000135446
Other databases
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=CDK4
Probes
Litterature
PubMed360 Pubmed reference(s) in Entrez
CoreMineCDK4
iHOPCDK4
OncoSearchCDK4

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
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written01-2007Anders Molven

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 online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/CDK4ID238ch12q14.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Tue Aug 26 15:28:31 CEST 2014

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