Alternative product of the p16/CKDN2A locus connects the Rb and p53 tumor suppressors.

Two distinct products are specified by the CDKN2A locus, the p16INK4a cyclin dependent kinase inhibitor and a protein termed ARF. ARF has been shown to bind to the Mdm2-p53 complex, resulting in stabilisation of both proteins, and a feedback loop exists through which ARF levels are negatively regulated by p53. Significantly, ARF expression is positively regulated by members of the E2F family of transcription factors. This provides a link between the Rb and p53 pathways and a mechanism whereby inactivation of Rb and release of E2F will lead to the stabilisation and functional activation of p53. The alternative exon encoding the functional amino terminal portion of ARF presumably represents an independent gene that has become co-localized with p16INK4a in order to exploit a common regulatory mechanism or purpose.