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cyclin-dependent kinase inhibitor 2A, isoform 4; p14ARF; p19ARF (MLM)

Function: - functions as growth & tumor suppressor & exerts actions upstream of p53 - binds to & inhibits mdm2 protein - Raf can induce both p14ARF & mdm2 protein - capable of inducing cell cycle arrest in G1 & G2phases - acts as a tumor suppressor - binds to MDM2 & blocks its nucleocytoplasmic shuttling by sequestering it in the nucleolus; this inhibits the oncogenic action of MDM2 by blocking MDM2-induced degradation of p53 & enhancing p53-dependent transactivation & apoptosis - also induces G2 arrest & apoptosis in a p53-independent manner by preventing the activation of cyclin B1/CDC2 complexes - binds to BCL6 & down-regulates BCL6-induced transcriptional repression - binds to E2F1 & MYC & blocks their transcriptional activator activity but has no effect on MYC transcriptional repression - binds to TOP1/TOPOI & stimulates its activity; complex binds to rRNA gene promoters & may play a role in rRNA transcription &/or maturation - interacts with NPM1/B23 & promotes its polyubiquitination & degradation, thus inhibiting rRNA processing - interacts with UBE2I/UBC9 & enhances sumoylation of a number of its binding partners including MDM2 & E2F1 - binds to HUWE1 & represses its ubiquitin ligase activity - may play a role in controlling cell proliferation & apoptosis during mammary gland development - does not interact with cyclins, CDC2, CDK2, CDK4, CDK5 or CDK6 - binds to BCL6, E2F1, HUWE1, MDM2, MYC, NPM1/B23, TOP1/TOPOI & UBE2I/UBC9 - interacts with TBRG1 - interacts with CDKN2AIP & E4F1 Compartment: nucleus, nucleolus (putative) Alternative splicing: named isoforms=4 Pathology: - may play a role in skeletal muscle satellite cell senecence - p16ink4A silencing by RNA interference restores regenerative capacity of satellite cells in old mice Comparative biology: - same as p19ARF in mice

Interactions

molecular events

Related

multiple tumor suppressor-1 (MTS1); INK4; CDKN2A gene

General

anti-oncoprotein (tumor suppressor protein) cyclin-dependent kinase inhibitor (CDKI, CDKN) human longevity protein nuclear protein phosphoprotein

Properties

SIZE: entity length = 173 aa MW = 18 kD COMPARTMENT: cell nucleus FORM: cyclin-dependent kinase inhibitor 2A, isoform 4 MOTIF: ankyrin repeat NAME: ankyrin repeat SITE: 11-40 ankyrin repeat NAME: ankyrin repeat SITE: 44-72 ankyrin repeat NAME: ankyrin repeat SITE: 77-106 ankyrin repeat NAME: ankyrin repeat SITE: 110-139 INHIBITS: protein kinase

References

  1. Ries S, Biederer C, Woods D, Shifman O, Shirasawa S, Sasazuki T, McMahon M, Oren M, McCormick F. Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF. Cell. 2000 Oct 13;103(2):321-30. PMID: 11057904
  2. UniProt :accession Q8N726
  3. NIEHS-SNPs http://egp.gs.washington.edu/data/cdkn2a/

Component-of

molecular complex

Databases & Figures

OMIM 600160 MORBIDMAP 600160 UniProt Q8N726 Pfam PF07392 Entrez Gene 1029 Figures/diagrams/slides/tables related to cyclin-dependent kinase inhibitor 2A, isoform 4