p14ARFp19ARF

p14ARFp19ARF refers to the ARF tumor suppressor proteins that are produced from the CDKN2A locus by an alternative reading frame. In humans, the product is called p14ARF; in mice, the ortholog is p19ARF. Both are small, around 14 kilodaltons, proteins that play a key role in activating the p53 tumor suppressor pathway in response to oncogenic stress. They are considered part of a conserved mechanism to prevent uncontrolled cell proliferation.

The primary function of ARF is to regulate the MDM2–p53 axis. ARF binds MDM2, inhibiting its E3 ubiquitin ligase activity that normally targets p53 for degradation. As a result, p53 accumulates and becomes activated, leading to transcription of p53 target genes such as CDKN1A/p21 that mediate cell cycle arrest, senescence, or apoptosis. ARF can also exert p53-independent effects in some contexts, contributing to growth control through alternative pathways and gene regulation.

ARF expression is tightly controlled and induced by oncogenic signals, notably by overexpression of Myc or Ras and other forms of oncogenic stress. The ARF promoter is subject to transcriptional regulation and can be silenced by epigenetic mechanisms or deletions. Because ARF and p16INK4a are encoded by the same CDKN2A locus but in different reading frames, genetic alterations at this locus can simultaneously disrupt both tumor suppressors, providing a potent pro-tumorigenic hit.

Clinical and research interest in p14ARF/p19ARF centers on their role in tumor suppression, their interaction with the p53 pathway, and their status in various cancers. While human and mouse ARFs are not identical, their core function in restraining cell growth in response to oncogenic stress is conserved.