ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence.
Inactivation of the p53 pathway represents the most common molecular defect of human cancer. But in the setting of melanoma, a highly aggressive and invariably fatal malignancy in its advanced disseminated form, mutation/deletion of p53 is relatively rare, whereas its positive regulator ARF is often lost. Here, we show that genetic deficiency in Arf but not p53 facilitates rapid development of melanoma in a genetically engineered mouse model. This difference is accounted for, at least in part, by the unanticipated observation that, unlike fibroblasts, senescence control in melanocytes is strongly regulated by Arf and not p53. Moreover, oncogenic NRAS collaborates with deficiency in Arf, but not p53, to fully transform melanocytes. Our data demonstrate that ARF and p53, although linked in a common pathway, suppress tumorigenesis through distinct, lineage-dependent mechanisms and suggest that ARF helps restrict melanoma progression by executing the oncogene-induced senescence program in benign nevi. Thus, therapeutics designed to restore wild-type p53 function may be insufficient to counter melanoma and other malignancies in which ARF holds p53-independent tumor suppressor activity.
Ha
Linan
L
Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892-4264, USA.
Ichikawa
Takeshi
T
Anver
Miriam
M
Dickins
Ross
R
Lowe
Scott
S
Sharpless
Norman E
NE
Krimpenfort
Paul
P
Depinho
Ronald A
RA
Bennett
Dorothy C
DC
Sviderskaya
Elena V
EV
Merlino
Glenn
G
D000818:Animals; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D004195:Disease Models, Animal; D008544:Melanocytes / Q000473:pathology; D008545:Melanoma / Q000209:etiology / Q000473:pathology*; D051379:Mice; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53
D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)