The INK4a/ARF gene locus on human chromosome 9p21, is one of the most frequent targets of inactivating mutations in the human tumors. Containing two different promoters, INK4a/ARF can encode two distinct proteins in alternative reading frames, p16^INK4a and p14^ARF (the mouse homologues is called p19^ARF). p16 is a recognized tumor suppressor that induces a G1 cell cycle arrest by inhibiting the phosphorylation of pRb by CDK4/6. While ARF inhibits oncoprotein MDM2, resulting in the stabilization of p53. These activities of ARF promote p53-mediated G1 and G2/M cell cycle arrests or apoptosis. So just like p16, the ARF protein also acts as a tumor suppressor.