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One reported function of the tumor suppressor p19Arf is to stabilize p53, providing a critical checkpoint in the response to oncogenic insults. Acute loss of Pten leads to an increase in the abundance of p19Arf, p53, and p21 proteins as part of a fail-safe senescence response. Here, we report that loss of p19Arf in prostate epithelium does not accelerate—but rather partially inhibits—the prostate cancer phenotype of Pten-deficient mice. Moreover, cellular senescence and a further decrease in the number of pre-neoplastic glands were observed in prostates of the Pten-p19Arf double-mutant mice. In both prostate epithelium and primary mouse embryo fibroblasts (MEFs), the increase in p53 protein abundance found upon loss of Pten was unaffected by the simultaneous loss of p19Arf. However, in contrast to that in the prostate epithelium, p19Arf deficiency in MEFs lacking Pten abolished cell senescence and promoted hyperproliferation and transformation despite the unabated increase in p53 abundance. Consistent with the effect of p19Arf loss in Pten-deficient mouse prostate, we found that in human prostate cancers, loss of PTEN was not associated with loss of p14ARF (the human equivalent of mouse p19Arf). Collectively, these data reveal differential consequences of p19Arf inactivation in prostate cancer and MEFs upon Pten loss that are independent of the p53 pathway.