THE INK4A ARF TUMOR-SUPPRESSOR - ONE GENE - 2 PRODUCTS - 2 PATHWAYS/

Functional inactivation of the retinoblastoma (RB) and p53 pathways ap pears to be a rite of passage for all cancerous cells and results in d isruption of cell-cycle regulation and deactivation of the apoptotic r esponse that normally ensues. The INK4a/ARF locus sits at the nexus of these two growth-control pathways, by virtue of its ability to genera te two distinct products: the p16(INK4a) protein, a cyclin-dependent k inase inhibitor that functions upstream of RE; and the p19(ARF) protei n, which blocks MDM2 inhibition of p53 activity. This 'one gene - two products - two pathways' arrangement provides a basis for the prominen ce of INK4a/ARF in tumorigenesis.