p16^INK4a and p53 deficiency cooperate in tumorigenesis

The combined impact of mutations in p16^INK4a and p53 was examined in cellular growth, transformation, and tumor formation. In cultured cells, p16^INK4a loss enhanced growth at high density and conferred susceptibility to oncogene-induced transformation. In vivo, mice doubly deficient for p16^INK4a and p53 showed an increased rate of tumor formation with particular susceptibility to aggressive angiosarcomas. Furthermore, p16^INK4a silencing by promoter methylation was detected in tumors derived from p16^INK4a+/- and^+/+ mice, independent of p53 status. These data suggest at least one general feature of malignancy, resistance to density-mediated growth arrest depends on p16^INK4a rather than p53. This cooperation between p16^INK4a and p53 loss in tumorigenesis is consistent with the view that these genes function in distinct anticancer pathways.