Loss of p16(Ink4a) with retention of p19(Arf) predisposes mice to tumorigenesis

The cyclin-dependent kinase inhibitor p16(INK4a) can induce senescence of h uman cells, and its loss by deletion, mutation or epigenetic silencing is a mong the most frequently observed molecular lesions in human cancer(1,2). O verlapping reading frames in the INK4A/ARF gene encode p16(INK4a) and a dis tinct tumour-suppressor protein, p19(ARF) (ref. 3). Here we describe the ge neration and characterization of a p16(Ink4a)-specific knockout mouse that retains normal p19(Arf) function. Mice lacking p16(Ink4a) were born with th e expected mendelian distribution and exhibited normal development except f or thymic hyperplasia. T cells deficient in p16(Ink4a) exhibited enhanced m itogenic responsiveness, consistent with the established role of p16(Ink4a) in constraining cellular proliferation. In contrast to mouse embryo fibrob lasts (MEFs) deficient in p19(Arf) (ref. 4), p16(Ink4a)-null MEFs possessed normal growth characteristics and remained susceptible to Ras-induced sene scence. Compared with wild-type MEFs, p16(Ink4a) null MEFs exhibited an inc reased rate of immortalization, although this rate was less than that obser ved previously for cells null for Ink4a/Arf, p19(Arf) or p53 (refs 4, 5). F urthermore, p16(Ink4a) deficiency was associated with an increased incidenc e of spontaneous and carcinogen-induced cancers. These data establish that p16(Ink4a), along with p19(Arf), functions as a tumour suppressor in mice.