Tbio CDKN2A Tumor suppressor ARF

Protein Summary

Description

Capable of inducing cell cycle arrest in G1 and G2 phases. Acts as a tumor suppressor. Binds to MDM2 and blocks its nucleocytoplasmic shuttling by sequestering it in the nucleolus. This inhibits the oncogenic action of MDM2 by blocking MDM2-induced degradation of p53 and enhancing p53-dependent transactivation and apoptosis. Also induces G2 arrest and apoptosis in a p53-independent manner by preventing the activation of cyclin B1/CDC2 complexes. Binds to BCL6 and down-regulates BCL6-induced transcriptional repression. Binds to E2F1 and MYC and blocks their transcriptional activator activity but has no effect on MYC transcriptional repression. Binds to TOP1/TOPOI and stimulates its activity. This complex binds to rRNA gene promoters and may play a role in rRNA transcription and/or maturation. Interacts with NPM1/B23 and promotes its polyubiquitination and degradation, thus inhibiting rRNA processing. Interacts with COMMD1 and promotes its 'Lys63'-linked polyubiquitination. Interacts with UBE2I/UBC9 and enhances sumoylation of a number of its binding partners including MDM2 and E2F1. Binds to HUWE1 and represses its ubiquitin ligase activity. May play a role in controlling cell proliferation and apoptosis during mammary gland development. Isoform smARF may be involved in regulation of autophagy and caspase-independent cell death; the short-lived mitochondrial isoform is stabilized by C1QBP. This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]

Uniprot Accession IDs

• Q8N726
• D3DRK2
• Q13195
• Q13399
• Q16360
• Q7KZR9

Gene Name

• CDKN2A

Ensembl ID

• ENST00000530628
• ENSP00000432664
• ENSG00000147889
• ENST00000579755
• ENSP00000462950

Symbol

• CDKN2
• MLM
• ARF
• MLM
• P14
• P16
• P19
• CMM2
• INK4
• MTS1
• TP16
• CDK4I
• CDKN2
• INK4A
• MTS-1
• P14ARF
• P19ARF
• P16INK4
• P16INK4A
• P16-INK4A

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
biological process	0
biological term	0
cell line	0
cell type or tissue	0
cellular component	0

Related Tools

Target Illumination GWAS Analytics (TIGA)

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IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 11825.2   (req: < 5)

Gene RIFs: 1908   (req: <= 3)

Antibodies: 1199   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 11825.2   (req: >= 5)

Gene RIFs: 1908   (req: > 3)

Antibodies: 1199   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 44

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligand: 0

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drug: 0

GWAS Traits (116)

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GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
coronary artery disease	EFO_0001645	7	7	4	1.2	98.6
coronary artery disease	EFO_0001645	7	7	4	1.2	98.6
cup-to-disc ratio measurement	EFO_0006939	4	5	14		98.6
cup-to-disc ratio measurement	EFO_0006939	4	5	14		98.6
open-angle glaucoma	EFO_0004190	10	9	0	1.3	98.1

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GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
coronary artery disease	EFO_0001645	4	1.2	98.6
coronary artery disease	EFO_0001645	4	1.2	98.6
cup-to-disc ratio measurement	EFO_0006939	14		98.6
cup-to-disc ratio measurement	EFO_0006939	14		98.6
open-angle glaucoma	EFO_0004190	0	1.3	98.1

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Orthologs (2)

1 – 2 of 2

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	cyclin dependent kinase inhibitor 2A		465021
Opossum	cyclin-dependent kinase inhibitor 2A		554242

Species	Name	OMA	EggNOG	Inparanoid
Chimp	cyclin dependent kinase inhibitor 2A
Opossum	cyclin-dependent kinase inhibitor 2A

Pathways (214)

Reactome (40)

KEGG (18)

PathwayCommons (8)

WikiPathways (148)

Cell Cycle (R-HSA-1640170)

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Data Source	Name	Explore in Pharos	Explore in Source
Reactome	Cell Cycle	597 targets	R-HSA-1640170
Reactome	Cell Cycle Checkpoints	272 targets	R-HSA-69620
Reactome	Cell Cycle, Mitotic	495 targets	R-HSA-69278
Reactome	Cellular Senescence	164 targets	R-HSA-2559583
Reactome	Cellular responses to external stimuli	487 targets	R-HSA-8953897

Name	Explore in Pharos	Explore in Source
Cell Cycle	597 targets	R-HSA-1640170
Cell Cycle Checkpoints	272 targets	R-HSA-69620
Cell Cycle, Mitotic	495 targets	R-HSA-69278
Cellular Senescence	164 targets	R-HSA-2559583
Cellular responses to external stimuli	487 targets	R-HSA-8953897

Gene Ontology Terms (49)

Functions (8)

Components (5)

Processes (36)

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GO Term	Evidence	Assigned by
SUMO transferase activity	Inferred from Experiment (EXP)	Reactome
ubiquitin ligase inhibitor activity	Inferred from Direct Assay (IDA)	CAFA
disordered domain specific binding	Inferred from Physical Interaction (IPI)	CAFA
MDM2/MDM4 family protein binding	Inferred from Physical Interaction (IPI)	UniProtKB
p53 binding	Inferred from Physical Interaction (IPI)	BHF-UCL
transcription factor binding	Inferred from Physical Interaction (IPI)	BHF-UCL
ubiquitin-protein transferase inhibitor activity	Inferred from Sequence or structural Similarity (ISS)	BHF-UCL
DNA binding	Inferred from Electronic Annotation (IEA)	UniProtKB-KW

Protein-Protein Interactions (595)

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1 – 10 of 595

• See Interactions on String-DB

CDK4

Tclin

Family:  Kinase

Novelty:  0.00036742

Score:  0.999

Data Source:  STRINGDB

CDK6

Tclin

Family:  Kinase

Novelty:  0.00109319

Score:  0.997

Data Source:  STRINGDB

TP53

Tchem

Family:  TF

Novelty:  0.00001907

Score:  0.997

Data Source:  Reactome,STRINGDB

MDM2

Tchem

Family:  Enzyme

Novelty:  0.00028385

Score:  0.993

Data Source:  Reactome,STRINGDB

MYC

Tchem

Family:  TF

Novelty:  0.00005734

Score:  0.993

Data Source:  STRINGDB

CCND1

Tchem

Novelty:  0.0001186

Score:  0.992

Data Source:  STRINGDB

E2F1

Tbio

Family:  TF

Novelty:  0.00277137

Score:  0.987

Data Source:  STRINGDB

RB1

Tchem

Novelty:  0.00063798

Score:  0.985

Data Source:  STRINGDB

HRAS

Tchem

Family:  Enzyme

Novelty:  0.00008069

Score:  0.984

Data Source:  STRINGDB

ORC5

Tbio

Novelty:  0.02264865

Score:  0.981

Data Source:  STRINGDB

Publication Statistics

PubMed Score  11825.20

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PubTator Score  6966.99

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Amino Acid Sequence

Residue Counts

Protein Sequence

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UniProt Keyword Find Similar Targets

No Header	No Header
Alternative splicing
Apoptosis
Cell cycle
Complete proteome
DNA-binding
Mitochondrion
Nucleus
Polymorphism
Reference proteome
rRNA processing

GWAS Trait Find Similar Targets

No Header	No Header
Abdominal Aortic Aneurysm
acute lymphoblastic leukemia
age at onset
ankle brachial index
Antiglaucoma preparations and miotics use measurement
Antithrombotic agent use measurement
apolipoprotein B measurement
aspirin use measurement
B-cell acute lymphoblastic leukemia
basal cell carcinoma

MGI Phenotype Find Similar Targets

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behavior/neurological phenotype
cellular phenotype
digestive/alimentary phenotype
endocrine/exocrine gland phenotype
hematopoietic system phenotype
homeostasis/metabolism phenotype
immune system phenotype
integument phenotype
mortality/aging
neoplasm