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CDK4 (cyclin-dependent kinase 4)

Written2007-01Anders Molven
Section for Pathology, The Gade Institute, Haukeland University Hospital, N-5021 Bergen, Norway

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)CMM3
MGC14458
PSK-J3
HGNC (Hugo) CDK4
HGNC Alias symbPSK-J3
LocusID (NCBI) 1019
Atlas_Id 238
Location 12q14.1  [Link to chromosome band 12q14]
Location_base_pair Starts at 57747727 and ends at 57752310 bp from pter ( according to GRCh38/hg38-Dec_2013)  [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 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CCND1 (11q13.3)::CDK4 (12q14.1)CDK4 (12q14.1)::ARV1 (1q42.2)CDK4 (12q14.1)::RPL4 (15q22.31)
CDK4 (12q14.1)::UBA1 (Xp11.23)CDK4 (12q14.1)::UBA1 (Xp11.3)

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
  
  
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 ]


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 6 ]
  del(9p) in Acute Lymphoblastic Leukemia
t(3;7)(q26;q21) CDK6::MECOM
t(5;7)(q35;q21) TLX3::CDK6
t(6;14)(p21;q32) IGH::CCND3
t(2;7)(p11;q21) IGK::CDK6::t(7;14)(q21;q32) IGH::CDK6::t(7;22)(q21;q11) IGL::CDK6::t(7;14)(q21;q11) TRA::CDK6
t(2;12)(p12;p13) IGK::CCND2::t(12;14)(p13;q32) IGH::CCND2::t(12;22)(p13;q11) IGL::CCND2


Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 3 ]
  Dysplastic nevus syndrome (DNS) Familial glioma Familial melanoma


External links

 

Nomenclature
HGNC (Hugo)CDK4   1773
LRG (Locus Reference Genomic)LRG_490
Cards
AtlasCDK4ID238ch12q14
Entrez_Gene (NCBI)CDK4    cyclin dependent kinase 4
AliasesCMM3; PSK-J3
GeneCards (Weizmann)CDK4
Ensembl hg19 (Hinxton)ENSG00000135446 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000135446 [Gene_View]  ENSG00000135446 [Sequence]  chr12:57747727-57752310 [Contig_View]  CDK4 [Vega]
ICGC DataPortalENSG00000135446
TCGA cBioPortalCDK4
AceView (NCBI)CDK4
Genatlas (Paris)CDK4
SOURCE (Princeton)CDK4
Genetics Home Reference (NIH)CDK4
Genomic and cartography
GoldenPath hg38 (UCSC)CDK4  -     chr12:57747727-57752310 -  12q14.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CDK4  -     12q14.1   [Description]    (hg19-Feb_2009)
GoldenPathCDK4 - 12q14.1 [CytoView hg19]  CDK4 - 12q14.1 [CytoView hg38]
ImmunoBaseENSG00000135446
Genome Data Viewer NCBICDK4 [Mapview hg19]  
OMIM123829   609048   
Gene and transcription
Genbank (Entrez)AK297901 AK310724 AK313701 BC003644 BC005864
RefSeq transcript (Entrez)NM_000075 NM_052984
Consensus coding sequences : CCDS (NCBI)CDK4
Gene ExpressionCDK4 [ NCBI-GEO ]   CDK4 [ EBI - ARRAY_EXPRESS ]   CDK4 [ SEEK ]   CDK4 [ MEM ]
Gene Expression Viewer (FireBrowse)CDK4 [ Firebrowse - Broad ]
GenevisibleExpression of CDK4 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1019
GTEX Portal (Tissue expression)CDK4
Human Protein AtlasENSG00000135446-CDK4 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP11802   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP11802  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP11802
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 ]   [ MEROPS ]
PhosPhoSitePlusP11802
Domaine pattern : Prosite (Expaxy)PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_ST (PS00108)   
Domains : Interpro (EBI)Kinase-like_dom_sf    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser/Thr_kinase_AS   
Domain families : Pfam (Sanger)Pkinase (PF00069)   
Domain families : Pfam (NCBI)pfam00069   
Domain families : Smart (EMBL)S_TKc (SM00220)  
Conserved Domain (NCBI)CDK4
PDB (RSDB)1LD2    2W96    2W99    2W9F    2W9Z    3G33    5FWK    5FWL    5FWM    5FWP    6P8E    6P8F    6P8G    6P8H   
PDB Europe1LD2    2W96    2W99    2W9F    2W9Z    3G33    5FWK    5FWL    5FWM    5FWP    6P8E    6P8F    6P8G    6P8H   
PDB (PDBSum)1LD2    2W96    2W99    2W9F    2W9Z    3G33    5FWK    5FWL    5FWM    5FWP    6P8E    6P8F    6P8G    6P8H   
PDB (IMB)1LD2    2W96    2W99    2W9F    2W9Z    3G33    5FWK    5FWL    5FWM    5FWP    6P8E    6P8F    6P8G    6P8H   
Structural Biology KnowledgeBase1LD2    2W96    2W99    2W9F    2W9Z    3G33    5FWK    5FWL    5FWM    5FWP    6P8E    6P8F    6P8G    6P8H   
SCOP (Structural Classification of Proteins)1LD2    2W96    2W99    2W9F    2W9Z    3G33    5FWK    5FWL    5FWM    5FWP    6P8E    6P8F    6P8G    6P8H   
CATH (Classification of proteins structures)1LD2    2W96    2W99    2W9F    2W9Z    3G33    5FWK    5FWL    5FWM    5FWP    6P8E    6P8F    6P8G    6P8H   
SuperfamilyP11802
AlphaFold pdb e-kbP11802   
Human Protein Atlas [tissue]ENSG00000135446-CDK4 [tissue]
HPRD00447
Protein Interaction databases
DIP (DOE-UCLA)P11802
IntAct (EBI)P11802
Complex Portal (EBI)P11802 CPX-2010 Cyclin D1-CDK4 complex
P11802 CPX-2011 Cyclin D2-CDK4 complex
P11802 CPX-2012 Cyclin D3-CDK4 complex
BioGRIDCDK4
STRING (EMBL)CDK4
ZODIACCDK4
Ontologies - Pathways
QuickGOP11802
Ontology : AmiGOG1/S transition of mitotic cell cycle  cyclin-dependent protein kinase holoenzyme complex  chromatin  lens development in camera-type eye  cyclin-dependent protein serine/threonine kinase activity  cyclin-dependent protein serine/threonine kinase activity  protein binding  ATP binding  nucleus  nucleus  nucleoplasm  nucleoplasm  transcription regulator complex  nucleolus  cytosol  cytosol  bicellular tight junction  protein phosphorylation  protein phosphorylation  signal transduction  circadian rhythm  positive regulation of cell population proliferation  RNA polymerase II CTD heptapeptide repeat kinase activity  response to toxic substance  response to lead ion  regulation of gene expression  positive regulation of G2/M transition of mitotic cell cycle  mediator complex  cyclin binding  granulocyte differentiation  animal organ regeneration  nuclear membrane  cellular response to insulin stimulus  response to testosterone  regulation of multicellular organism growth  response to drug  positive regulation of apoptotic process  protein-containing complex binding  positive regulation of translation  positive regulation of cell cycle  positive regulation of cell size  regulation of insulin receptor signaling pathway  regulation of lipid biosynthetic process  positive regulation of fibroblast proliferation  perinuclear region of cytoplasm  regulation of lipid catabolic process  cell division  regulation of cell cycle  regulation of cell cycle  response to hyperoxia  regulation of transcription initiation from RNA polymerase II promoter  adipose tissue development  cellular response to lipopolysaccharide  cellular response to interleukin-4  cyclin D2-CDK4 complex  protein serine kinase activity  protein threonine kinase activity  cellular response to phorbol 13-acetate 12-myristate  cellular response to ionomycin  negative regulation of G1/S transition of mitotic cell cycle  
Ontology : EGO-EBIG1/S transition of mitotic cell cycle  cyclin-dependent protein kinase holoenzyme complex  chromatin  lens development in camera-type eye  cyclin-dependent protein serine/threonine kinase activity  cyclin-dependent protein serine/threonine kinase activity  protein binding  ATP binding  nucleus  nucleus  nucleoplasm  nucleoplasm  transcription regulator complex  nucleolus  cytosol  cytosol  bicellular tight junction  protein phosphorylation  protein phosphorylation  signal transduction  circadian rhythm  positive regulation of cell population proliferation  RNA polymerase II CTD heptapeptide repeat kinase activity  response to toxic substance  response to lead ion  regulation of gene expression  positive regulation of G2/M transition of mitotic cell cycle  mediator complex  cyclin binding  granulocyte differentiation  animal organ regeneration  nuclear membrane  cellular response to insulin stimulus  response to testosterone  regulation of multicellular organism growth  response to drug  positive regulation of apoptotic process  protein-containing complex binding  positive regulation of translation  positive regulation of cell cycle  positive regulation of cell size  regulation of insulin receptor signaling pathway  regulation of lipid biosynthetic process  positive regulation of fibroblast proliferation  perinuclear region of cytoplasm  regulation of lipid catabolic process  cell division  regulation of cell cycle  regulation of cell cycle  response to hyperoxia  regulation of transcription initiation from RNA polymerase II promoter  adipose tissue development  cellular response to lipopolysaccharide  cellular response to interleukin-4  cyclin D2-CDK4 complex  protein serine kinase activity  protein threonine kinase activity  cellular response to phorbol 13-acetate 12-myristate  cellular response to ionomycin  negative regulation of G1/S transition of mitotic cell cycle  
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   
REACTOMEP11802 [protein]
REACTOME PathwaysR-HSA-912446 [pathway]   
NDEx NetworkCDK4
Atlas of Cancer Signalling NetworkCDK4
Wikipedia pathwaysCDK4
Orthology - Evolution
OrthoDB1019
GeneTree (enSembl)ENSG00000135446
Phylogenetic Trees/Animal Genes : TreeFamCDK4
Homologs : HomoloGeneCDK4
Homology/Alignments : Family Browser (UCSC)CDK4
Gene fusions - Rearrangements
Fusion : MitelmanCDK4::UBA1 [12q14.1/Xp11.23]  
Fusion : QuiverCDK4
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCDK4 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CDK4
dbVarCDK4
ClinVarCDK4
MonarchCDK4
1000_GenomesCDK4 
Exome Variant ServerCDK4
GNOMAD BrowserENSG00000135446
Varsome BrowserCDK4
ACMGCDK4 variants
VarityP11802
Genomic Variants (DGV)CDK4 [DGVbeta]
DECIPHERCDK4 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCDK4 
Mutations
ICGC Data PortalCDK4 
TCGA Data PortalCDK4 
Broad Tumor PortalCDK4
OASIS PortalCDK4 [ Somatic mutations - Copy number]
Cancer Gene: CensusCDK4 
Somatic Mutations in Cancer : COSMICCDK4  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DCDK4
Mutations and Diseases : HGMDCDK4
intOGen PortalCDK4
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
BioMutaCDK4
DgiDB (Drug Gene Interaction Database)CDK4
DoCM (Curated mutations)CDK4
CIViC (Clinical Interpretations of Variants in Cancer)CDK4
OncoKBCDK4
NCG (London)CDK4
Cancer3DCDK4
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM123829    609048   
Orphanet3560    14544    14543   
DisGeNETCDK4
MedgenCDK4
Genetic Testing Registry CDK4
NextProtP11802 [Medical]
GENETestsCDK4
Target ValidationCDK4
Huge Navigator CDK4 [HugePedia]
ClinGenCDK4
Clinical trials, drugs, therapy
MyCancerGenomeCDK4
Protein Interactions : CTDCDK4
Pharm GKB GenePA102
PharosP11802
Drug Sensitivity CDK4
Clinical trialCDK4
Miscellaneous
canSAR (ICR)CDK4
HarmonizomeCDK4
DataMed IndexCDK4
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=CDK4
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXCDK4
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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