Alternate reading frame tumor suppressor protein p14ARF (p14ARF)

Alternate reading frame tumor suppressor protein p14ARF (p14ARF) is a human tumor suppressor encoded by an alternative reading frame of the CDKN2A locus, distinct from but overlapping with p16INK4a.[1][3][5][7][9] It is a small, highly basic nucleolar protein that is induced in response to oncogenic or excessive mitogenic signaling and accumulates mainly in the nucleolus, where it forms complexes with MDM2 (HDM2) and nucleophosmin (NPM).[1][3][5][9] By binding and sequestering MDM2, p14ARF prevents MDM2-mediated ubiquitination, nuclear export, and degradation of p53, thereby stabilizing and activating p53 and promoting transcription of genes that induce cell-cycle arrest and apoptosis.[1][2][5][7][8][9][11] p14ARF can also suppress cell growth through p53-independent mechanisms, including delaying S-phase progression and modulating ribosome biogenesis by inhibiting rRNA processing via interaction with NPM.[1][3][5][8] The CDKN2A locus producing p14ARF is one of the most frequently deleted, mutated, or epigenetically silenced regions in human cancers, and loss of p14ARF contributes to loss of p53 function and uncontrolled proliferation.[1][2][3][5][7] Clinically, p14ARF expression has been investigated as a prognostic biomarker in several cancers (e.g., head and neck squamous cell carcinoma), where absence of p14ARF protein correlates with poorer disease-free and overall survival.[6] Experimental data indicate that p14ARF is SUMOylated despite lacking lysine residues, and that its SUMOylation and stabilization can contribute to the cytotoxic effects of the NEDD8-activating enzyme inhibitor MLN4924 (pevonedistat), linking p14ARF to therapeutic response in some tumor contexts.[4]

Other names

Tumor suppressor ARFARF tumor suppressorARFCyclin-dependent kinase inhibitor 2A, isoform p14ARF (CDKN2A p14ARF)p14(ARF)

For MLN4924 (pevonedistat): inhibition of cullin–RING ligases via NEDD8-activating enzyme blockade leads to stabilization of multiple tumor suppressors including p14ARF; p14ARF SUMOylation and stabilization contribute to MLN4924-driven cytotoxicity in cancer cells