CDK4 (cyclin-dependent kinase 4)

2007-01-01   Anders Molven 

Section for Pathology, The Gade Institute, Haukeland University Hospital, N-5021 Bergen, Norway

Identity

HGNC
LOCATION
12q14.1
LOCUSID
FUSION GENES

DNA/RNA

Atlas Image
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.

Proteins

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 name
Familial cutaneous malignant melanoma 3 (CMM3)
Note
Cases with wild-type BRAF and NRAS genes
Entity name
Glioma
Disease
Anaplastic astrocytoma and glioblastoma multiforme
Entity name
Sarcoma
Disease
In particular liposarcoma, alveolar rhabdomyosarcoma and osteosarcoma

Bibliography

Pubmed IDLast YearTitleAuthors
162919832005Distinct sets of genetic alterations in melanoma.Curtin JA et al
82216951993Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas.Khatib ZA et al
162365192005Mammalian cyclin-dependent kinases.Malumbres M et al
158805892005A large Norwegian family with inherited malignant melanoma, multiple atypical nevi, and CDK4 mutation.Molven A et al
80447751994Amplification 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 et al
94076261998Molecular changes during the genesis of human gliomas.Sehgal A et al
94252281998Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The French Familial Melanoma Study Group.Soufir N et al
85282631996Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma.Zuo L et al

Other Information

Locus ID:

NCBI: 1019
MIM: 123829
HGNC: 1773
Ensembl: ENSG00000135446

Variants:

dbSNP: 1019
ClinVar: 1019
TCGA: ENSG00000135446
COSMIC: CDK4

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000135446ENST00000257904P11802
ENSG00000135446ENST00000257904A0A024RBB6
ENSG00000135446ENST00000312990Q96BE9
ENSG00000135446ENST00000546489F8VZ51
ENSG00000135446ENST00000547281F8VZZ0
ENSG00000135446ENST00000549606F8VZ13
ENSG00000135446ENST00000550419F8VTV8
ENSG00000135446ENST00000551800F8VXD2
ENSG00000135446ENST00000552254F8VWX7
ENSG00000135446ENST00000552388F8VYH9
ENSG00000135446ENST00000552862F8W1L8
ENSG00000135446ENST00000553237F8VYY1

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
Cell cycleKEGGko04110
p53 signaling pathwayKEGGko04115
Tight junctionKEGGko04530
T cell receptor signaling pathwayKEGGko04660
Pancreatic cancerKEGGko05212
GliomaKEGGko05214
MelanomaKEGGko05218
Bladder cancerKEGGko05219
Chronic myeloid leukemiaKEGGko05220
Small cell lung cancerKEGGko05222
Non-small cell lung cancerKEGGko05223
Cell cycleKEGGhsa04110
p53 signaling pathwayKEGGhsa04115
Tight junctionKEGGhsa04530
T cell receptor signaling pathwayKEGGhsa04660
Pathways in cancerKEGGhsa05200
Pancreatic cancerKEGGhsa05212
GliomaKEGGhsa05214
MelanomaKEGGhsa05218
Bladder cancerKEGGhsa05219
Chronic myeloid leukemiaKEGGhsa05220
Small cell lung cancerKEGGhsa05222
Non-small cell lung cancerKEGGhsa05223
MeaslesKEGGko05162
MeaslesKEGGhsa05162
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Hepatitis BKEGGhsa05161
Cell cycle - G1/S transitionKEGGhsa_M00692
Cell cycle - G1/S transitionKEGGM00692
Signal TransductionREACTOMER-HSA-162582
Cell CycleREACTOMER-HSA-1640170
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G1-G1/S phasesREACTOMER-HSA-453279
G1 PhaseREACTOMER-HSA-69236
Cyclin D associated events in G1REACTOMER-HSA-69231
G1/S TransitionREACTOMER-HSA-69206
Cyclin E associated events during G1/S transitionREACTOMER-HSA-69202
SCF(Skp2)-mediated degradation of p27/p21REACTOMER-HSA-187577
S PhaseREACTOMER-HSA-69242
Cyclin A:Cdk2-associated events at S phase entryREACTOMER-HSA-69656
Ubiquitin-dependent degradation of Cyclin DREACTOMER-HSA-75815
Ubiquitin-dependent degradation of Cyclin D1REACTOMER-HSA-69229
MeiosisREACTOMER-HSA-1500620
Meiotic recombinationREACTOMER-HSA-912446
Developmental BiologyREACTOMER-HSA-1266738
Transcriptional regulation of white adipocyte differentiationREACTOMER-HSA-381340
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
Oncogene Induced SenescenceREACTOMER-HSA-2559585
Oxidative Stress Induced SenescenceREACTOMER-HSA-2559580
Senescence-Associated Secretory Phenotype (SASP)REACTOMER-HSA-2559582
Chromatin organizationREACTOMER-HSA-4839726
Chromatin modifying enzymesREACTOMER-HSA-3247509
RMTs methylate histone argininesREACTOMER-HSA-3214858
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933
Signaling by PTK6REACTOMER-HSA-8848021
PTK6 Regulates Cell CycleREACTOMER-HSA-8849470
Endocrine resistanceKEGGko01522
Endocrine resistanceKEGGhsa01522
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA445968Turner SyndromeDiseaseClinicalAnnotationassociatedPD23567489
PA451446somatropin recombinantChemicalClinicalAnnotationassociatedPD23567489

References

Pubmed IDYearTitleCitations
250020282014CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors.128
203541912010Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts.127
164134692006Requirement for CDK4 kinase function in breast cancer.116
169493662006Structure of an Hsp90-Cdc37-Cdk4 complex.116
120773432002A two-stage, p16(INK4A)- and p53-dependent keratinocyte senescence mechanism that limits replicative potential independent of telomere status.101
212782462011Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer.100
170470422006High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL.97
209519432010Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase.96
291603102018Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance.90
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85

Citation

Anders Molven

CDK4 (cyclin-dependent kinase 4)

Atlas Genet Cytogenet Oncol Haematol. 2007-01-01

Online version: http://atlasgeneticsoncology.org/gene/238/cdk4-(cyclin-dependent-kinase-4)