ALTERNATIVE READING FRAMES OF THE INK4A TUMOR-SUPPRESSOR GENE ENCODE 2 UNRELATED PROTEINS CAPABLE OF INDUCING CELL-CYCLE ARREST

The INK4a (MTS1, CDKN2) gene encodes an inhibitor (p16(INK4a)) Of the cyclin D-dependent kinases CDK4 and CDK6 that blocks them from phospho rylating the retinoblastoma protein (pRB) and prevents exit from the G 1 phase of the cell cycle. Deletions and mutations involving INK4a occ ur frequently in cancers, implying that p16(INK4a), like pRB, suppress es tumor formation. An unrelated protein (p19(ARF)) arises in major pa rt from an alternative reading frame of the mouse INK4a gene, and its ectopic expression in the nucleus of rodent fibroblasts induces G1 and G2 phase arrest. Economical reutilization of coding sequences in this manner is practically without precedent in mammalian genomes, and the unitary inheritance of p16(INK4a) and p19(ARF) may underlie their dua l requirement in cell cycle control.