ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence

摘要: Inactivation of the p53 pathway represents most common molecular defect human cancer. But in setting melanoma, a highly aggressive and invariably fatal malignancy its advanced disseminated form, mutation/deletion is relatively rare, whereas positive regulator ARF often lost. Here, we show that genetic deficiency Arf but not facilitates rapid development melanoma genetically engineered mouse model. This difference accounted for, at least part, by unanticipated observation that, unlike fibroblasts, senescence control melanocytes strongly regulated p53. Moreover, oncogenic NRAS collaborates with Arf, p53, to fully transform melanocytes. Our data demonstrate although linked pathway, suppress tumorigenesis through distinct, lineage-dependent mechanisms suggest helps restrict progression executing oncogene-induced program benign nevi. Thus, therapeutics designed restore wild-type function may be insufficient counter other malignancies which holds p53-independent tumor suppressor activity.