Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis

Abstract

The cyclin-dependent kinase inhibitor p16^INK4a can induce senescence of human cells, and its loss by deletion, mutation or epigenetic silencing is among the most frequently observed molecular lesions in human cancer^1,2. Overlapping reading frames in the INK4A/ARF gene encode p16^INK4a and a distinct tumour-suppressor protein, p19^ARF (ref. 3). Here we describe the generation and characterization of a p16^Ink4a-specific knockout mouse that retains normal p19^Arf function. Mice lacking p16^Ink4a were born with the expected mendelian distribution and exhibited normal development except for thymic hyperplasia. T cells deficient in p16^Ink4a exhibited enhanced mitogenic responsiveness, consistent with the established role of p16^Ink4a in constraining cellular proliferation. In contrast to mouse embryo fibroblasts (MEFs) deficient in p19^Arf (ref. 4), p16^Ink4a-null MEFs possessed normal growth characteristics and remained susceptible to Ras-induced senescence. Compared with wild-type MEFs, p16^Ink4a-null MEFs exhibited an increased rate of immortalization, although this rate was less than that observed previously for cells null for Ink4a/Arf, p19^Arf or p53 (refs 4, 5). Furthermore, p16^Ink4a deficiency was associated with an increased incidence of spontaneous and carcinogen-induced cancers. These data establish that p16^Ink4a, along with p19^Arf, functions as a tumour suppressor in mice.