The INK4a/ARF tumor suppressor: one gene--two products--two pathways.

Functional inactivation of the retinoblastoma (RB) and p53 pathways appears to be a rite of passage for all cancerous cells and results in disruption of cell-cycle regulation and deactivation of the apoptotic response that normally ensues. The INK4a/ARF locus sits at the nexus of these two growth-control pathways, by virtue of its ability to generate two distinct products: the p16INK4a protein, a cyclin-dependent kinase inhibitor that functions upstream of RB; and the p19ARF protein, which blocks MDM2 inhibition of p53 activity. This 'one gene--two products--two pathways' arrangement provides a basis for the prominence of INK4a/ARF in tumorigenesis.