Abstract 1575: ARF regulates the stability of p16 protein via REGγ-dependent proteasome degradation

Abstract The cell cycle regulatory gene INK4A-ARF (CDKN2A) has two alternative transcripts that produce entirely different proteins, namely p14ARF and p16, which have complementary functions as regulators of p53 and pRB tumor suppressor pathways, respectively. The unusual organization of INK4A-ARF has long led to speculation of a need for coordinated regulation of p14ARF and p16. We now show that p14ARF (ARF) regulates the stability of p16 protein in human cancer cell lines, as well as in mouse embryonic fibroblasts (MEFs). In particular, ARF promotes rapid degradation of p16 protein, which is mediated by the proteasome and, more specifically, by interaction of ARF with one of its subunits, REGγ. Furthermore, this ARF-dependent destabilization of p16 can be abrogated by knock-down of REGγ or by pharmacological blockade of its nuclear export. Thus our findings have uncovered a novel crosstalk of two key tumor suppressors mediated by a REGγ-dependent mechanism. Citation Format: Takashi Kobayashi, Osamu Ogawa, Cory Abate-Shen. ARF regulates the stability of p16 protein via REGγ-dependent proteasome degradation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1575. doi:10.1158/1538-7445.AM2014-1575