P14arf

This article is about a tumor suppressor gene. For ARF small GTP-binding protein, see ADP ribosylation factor.
cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)
Identifiers
SymbolCDKN2A
Alt. symbolsCDKN2, MLM
NCBI gene1029
HGNC1787
OMIM600160
RefSeqNM_058195
UniProtP42771
Other data
LocusChr. 9 p21
Search for
StructuresSwiss-model
DomainsInterPro

p14ARF (also called ARF tumor suppressor, ARF, p14ARF) is an alternate reading frame protein product of the CDKN2A locus (i.e. INK4a/ARF locus).[1] p14ARF is induced in response to elevated mitogenic stimulation, such as aberrant growth signaling from MYC and Ras (protein).[2] It accumulates mainly in the nucleolus where it forms stable complexes with NPM or Mdm2. These interactions allow p14ARF to act as a tumor suppressor by inhibiting ribosome biogenesis or initiating p53-dependent cell cycle arrest and apoptosis, respectively.[3] p14ARF is an atypical protein, in terms of its transcription, its amino acid composition, and its degradation: it is transcribed in an alternate reading frame of a different protein, it is highly basic,[1] and it is polyubiquinated at the N-terminus.[4]

Both p16INK4a and p14ARF are involved in cell cycle regulation. p14ARF inhibits mdm2, thus promoting p53, which promotes p21 activation, which then binds and inactivates certain cyclin-CDK complexes, which would otherwise promote transcription of genes that would carry the cell through the G1/S checkpoint of the cell cycle. Loss of p14ARF by a homozygous mutation in the CDKN2A (INK4A) gene will lead to elevated levels in mdm2 and, therefore, loss of p53 function and cell cycle control.

The equivalent in mice is p19ARF.

  1. ^ a b Sherr CJ (September 2006). "Divorcing ARF and p53: an unsettled case". Nat. Rev. Cancer. 6 (9): 663–73. doi:10.1038/nrc1954. PMID 16915296. S2CID 29465278.
  2. ^ Abida WM, Gu W (January 2008). "p53-Dependent and p53-independent activation of autophagy by ARF". Cancer Res. 68 (2): 352–7. doi:10.1158/0008-5472.CAN-07-2069. PMC 3737745. PMID 18199527.
  3. ^ Sherr CJ (May 2006). "Autophagy by ARF: a short story". Mol. Cell. 22 (4): 436–7. doi:10.1016/j.molcel.2006.05.005. PMID 16713573.
  4. ^ Kuo ML, den Besten W, Bertwistle D, Roussel MF, Sherr CJ (August 2004). "N-terminal polyubiquitination and degradation of the Arf tumor suppressor". Genes Dev. 18 (15): 1862–74. doi:10.1101/gad.1213904. PMC 517406. PMID 15289458.