p14ARF
p14^ARF, encoded by the CDKN2A locus, is a tumor suppressor that binds MDM2, the ubiquitin ligase that degrades p53, and holds it in the nucleolus.
Function
ARF responds to hyperproliferative signals - oncogene activation, E2F overactivity - rather than to DNA damage. Activated ARF binds MDM2 in the nucleolus, holding it away from p53; p53 stabilizes and accumulates, and the cell arrests or dies. DNA damage signals through ATM to p53, while oncogene activation signals through ARF to p53, so a cell faces p53-mediated arrest whether its genome is damaged or its growth signaling is activated by an oncogene. The mouse homolog, p19^ARF, serves the same role with different biochemistry.
In cancer
ARF shares the CDKN2A locus with p16, encoded in an alternative reading frame of the same DNA - a rare genetic arrangement that puts two tumor suppressors in the space of one gene. Deletion of the locus removes both at once, which is why CDKN2A loss is so frequent in cancer. ARF promoter methylation occurs in colon and gastric tumors with intact p16, and ARF loss cooperates with MYC overexpression in lymphoma models.
Notes
- Human gene symbol: CDKN2A (alternative reading frame product); UniProt Q8N726; 132 amino acids; nucleolar localization.