p19ARF

p19ARF is the protein product of the Arf gene in mice, produced by an alternative reading frame of the Cdkn2a locus. In humans, the orthologous product is p14ARF, encoded by the same genomic region via a different reading frame. Both p19ARF and p14ARF are small tumor suppressors that become activated in response to oncogenic stress and help preserve genomic integrity.

The primary function of ARF proteins is to regulate the p53 tumor suppressor pathway. ARF binds to MDM2, an E3 ubiquitin ligase that targets p53 for degradation, and promotes MDM2's sequestration in the nucleolus. This reduces p53 ubiquitination, leading to stabilization and activation of p53. As a result, cells can undergo p53-dependent cell cycle arrest, senescence, or apoptosis in response to oncogenic signals. ARF can also influence cell fate through p53-independent mechanisms by interacting with other cell cycle regulators.

Expression of ARF is typically low in most normal tissues but is upregulated by oncogenic signals such as aberrant Myc or Ras activity. In cancer, the Cdkn2a/Arf locus is frequently inactivated by deletions, mutations, or promoter methylation. Because this locus also encodes p16INK4a, cancers often lose both ARF and INK4A functions, though selective loss of ARF alone is observed in some tumors.

Research use highlights the role of p19ARF/p14ARF in regulating the p53 pathway and in mediating responses to cellular stress. While the two proteins are species-specific products of the same genomic region, they perform analogous tumor-suppressive functions and are studied to understand mechanisms of tumor suppression and potential therapeutic implications.