TUMOR SUPPRESSION AT THE MOUSE INK4A LOCUS MEDIATED BY THE ALTERNATIVE READING FRAME PRODUCT P19(ARF)

The INK4a tumor suppressor locus encodes p16(INK4a), an inhibitor of c yclin D-dependent kinases, and p19(ARF), an alternative reading frame protein that also blocks cell proliferation. Surprisingly, mice lackin g p19(ARF) but expressing functional p16(INK4a) develop tumors early i n life. Their embryo fibroblasts (MEFs) do not senesce and are transfo rmed by oncogenic Ha-ras alone. Conversion of ARF(+/+) or ARF(+/-) MEF strains to continuously proliferating cell lines involves loss of eit her p19(ARF) or p53. p53-mediated checkpoint control is unperturbed in ARF-null fibroblast strains, whereas p53-negative cell lines are resi stant to p19(ARF)-induced growth arrest. Therefore, INK4a encodes grow th inhibitory proteins that act upstream of the retinoblastoma protein and p53. Mutations and deletions targeting this locus in cancer cells are unlikely to be functionally equivalent.