Oncogenes & Tumor Suppressors ARF Regulates the Stability of p16 Protein Via REGg- Dependent Proteasome Degradation

The cell-cycle regulatory gene INK4A-ARF (CDKN2A) has two alternative transcripts that produce entirely different proteins, namely p14 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 p14 and p16.We now show that p14 (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 ismediated by the proteasome and,more specifically, by interaction of ARF with one of its subunits, REGg . Furthermore, this ARF-dependent destabilization of p16 can be abrogated by knockdown ofREGg or by pharmacologic blockade of its nuclear export. Thus, our findings have uncovered a novel crosstalk of 2 key tumor suppressorsmediated by aREGg-dependentmechanism.The ability of ARF to control p16 stability may influence cell-cycle function. Implications: The ability of ARF to control p16 stability may influence cell cycle function. Visual Overview: http://mcr.aacrjournals.org/content/11/8/828/F1.large.jpg. Mol Cancer Res; 11(8); 828–33.