p14ARF

p14ARF, also known as ARF or p14ARF, is a tumor suppressor protein encoded by the CDKN2A gene in humans. It arises from an alternative reading frame of the CDKN2A transcript, using exon 1β, and translates into a protein of about 132 amino acids (~14 kDa). The human p14ARF is the ortholog of mouse p19ARF.

Genomic context and expression: The CDKN2A locus on chromosome 9p21 encodes two distinct tumor suppressors through alternative reading frames: p16INK4a and p14ARF. p14ARF expression is typically induced in response to oncogenic stress, such as deregulated E2F1 signaling and oncogenic Ras or Myc activity, linking abnormal proliferation signals to cell cycle control.

Function and mechanism: The principal role of p14ARF is to modulate the p53 tumor suppressor pathway. It binds to MDM2, inhibiting MDM2’s ubiquitin ligase activity and preventing p53 degradation. This stabilization of p53 leads to cell cycle arrest or apoptosis in response to oncogenic cues. In addition to p53-dependent effects, p14ARF has p53-independent roles, including influences on ribosome biogenesis and chromatin remodeling, and interactions with nucleolar proteins such as nucleophosmin (B23).

Clinical significance: Inactivation or loss of CDKN2A/p14ARF is common in cancers, frequently through deletion of 9p21 or promoter methylation. Loss of p14ARF disrupts p53 regulation and promotes tumorigenesis, even in tumors with wild-type p53, by enabling MDM2-mediated p53 suppression and alternative pro-tumorigenic pathways. The 9p21 region is a well-recognized deletion hotspot in multiple cancer types.