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FLASH GENE

Symbol

CDK4

contributors: mct/ - updated : 12-02-2019

HGNC name	cyclin-dependent kinase 4
HGNC id	1773

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CMM3 hereditary malignant melanoma
Location	12q14.1      Physical location : 58.142.004 - 58.146.164
Synonym name	cell division kinase 4
Synonym symbol(s)	MGC14458, PSK-J3, CMM3
EC.number	2.7.11.22

DNA

TYPE	functioning gene
STRUCTURE	4.72 kb     8 Exon(s)

10 Kb 5' upstream gene genomic sequence study

text structure

Exons coding : 7

MAPPING

cloned

Y

linked

N

status

confirmed

Map

cen - D12S1707 - D12S1410 - RPS26 - D12S1177E - D12S1644 - D12S1268 - DDIT3 DDIT3 , GLI - B4GALNT1 - KIF5A - TSPAN31 - CDK4 - D12S1197E - D12S90 - D12S1529 - D12S1438 - (D12S305 ,D12S104 ) - D12S72 - D12S1446 - D12S1829 - D12S355 - D12S1298 - D12S1277 - D12S1989 - D12S1700 - D12S1169E - D12S1072 - D12S1662 - D12S83 - qter

RNA

TRANSCRIPTS	type	messenger

text	two alternatively spliced variants and multiple polyadenylation sites

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000075 8 - 1474 NP_000066 33.6 303 - 2009 19237565 NM_052984 - - 1122 NP_443710 - 111 - -

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Digestive liver       highly Nervous brain       highly Respiratory lung       highly Urinary kidney       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective         Muscular striatum skeletal

cell lineage

cell lines

fluid/secretion

at STAGE

cell cycle

cell cycle, checkpoint, G1S

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

a PV/ISTVRE motif

HOMOLOGY

interspecies

ortholog to yeast S.cerevisiae cdc28

Homologene

FAMILY	protein kinase superfamily
	CMGC Ser/Thr protein kinase family
	CDC2/CDKX subfamily

CATEGORY

enzyme , tumor suppressor

SUBCELLULAR LOCALIZATION	plasma membrane,junction,tight
	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus,chromatin/chromosome
	intracellular,nucleus,nucleolus

basic FUNCTION	serine/threonine kinase, involved in cell cycle regulation (G1 to S transition)
	essential for the G1- to S-phase transition during the cell cycle and its expression is primarily controlled at the transcriptional level
	key regulator of the transition through the G(1) phase of the cell cycle
	controls beta-cell mass by recruiting quiescent cells to enter the cell cycle
	plays a previously unrecognized role in thymocyte maturation and adhesion, but is not required for thymocyte proliferation and is not required for lymphocyte trafficking to the lung following allergen sensitization and challenge ((
	CCND1-CDK4 axis is not only critical in glial tumor cells but also in stromal-derived cells in the surrounding tumor microenvironment that are vital to sustain tumor outgrowth

CELLULAR PROCESS	cell cycle, progression
	nucleotide, repair

PHYSIOLOGICAL PROCESS

text	negative control

PATHWAY

metabolism

signaling

a component	complexing with cyclins D (D1, D2, D3)
	cyclin D2 and CDK4 formed a complex in the cytoplasm and approached the nucleus
	CDK2/CDK4/NPM pathway is a major guardian of centrosome dysfunction and genomic integrity
	CCND1-CDK4 axis is not only critical in glial tumor cells but also in stromal-derived cells in the surrounding tumor microenvironment that are vital to sustain tumor outgrowth

INTERACTION

DNA

RNA

small molecule

protein	target by MYC phosphorylating and blocking active repression by RB1
	ZNF655
	bound to cyclin D1 and has a phosphorylated T-loop, but is in an inactive conformation
	YY1 inhibited CDKN1A complex formation with CDK4 and CCND1
	UCHL1 physically interacts with CDK1, CDK4, and CDK5, enhancing their kinase activity
	novel function of CCND1 in promoting cell cycle progression by enhancing STK38/STK38L kinase activity independent of CDK4
	RUNX1T1 controls proliferation and the neurotoxic effect of microglia by epigenetically regulating CDK4 and LAT2 via its interaction with HDACs
	CIAPIN1 played an important role in the proliferation of liver cancer cells through increasing the expressions of cell cycle related proteins CCND1, CDK2, CDK4, and CCNE1
	SHCBP1 promoted cell cycle progression by regulating the CDK4&
	8209;CCND1 cascade and suppressed CASP3, caspase PARP&
	8209;dependent apoptotic pathways
	RPS14 can act as a CDK4/6 inhibitor linking ribosome biogenesis defects to the main engine of cell cycle progression
	CDK4/CDK6 regulate lysosome biogenesis through TFEB/TFE3

cell & other

REGULATION

inhibited by

PPP3CA (inhibits the kinase activity of CDK4 by preventing its reassociation into an active kinase complex by utilizing common association domains used by cyclin D and CDKN2A)

repressed by

JUND (increased JunD in polyamine-deficient cells was associated with a significant inhibition of CDK4 transcription, as indicated by repression of CDK4-promoter activity and decreased levels of CDK4 mRNA and protein)

ASSOCIATED DISORDERS

corresponding disease(s)

CMM3

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral   amplification     in malignant glioblastoma, anaplastic astrocytoma, in diffuse large B cell lymphoma, osteosarcoma with OS9, SAS and PRIM1 and in sporadic breast carcinoma constitutional     --low   in insulin deficient diabete

Susceptibility

predisposing to familial melanoma by inducing abnormal repair of ultraviolet

Variant & Polymorphism

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

Cdk4-deficient mice display beta-cell hypoplasia and develop diabetes, whereas beta-cell hyperplasia is observed in mice expressing an active Cdk4R24C kinase