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

More general terms

• p16ink4A

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=1029
• OMIM: https://mirror.omim.org/entry/600160
• UniProt: http://www.uniprot.org/uniprot/Q8N726.html