p53 prevents progression of nevi to melanoma predominantly through cell cycle regulation.
p53 is the central member of a critical tumor suppressor pathway in virtually all tumor types, where it is silenced mainly by missense mutations. In melanoma, p53 predominantly remains wild type, thus its role has been neglected. To study the effect of p53 on melanocyte function and melanomagenesis, we crossed the ‘high-p53’Mdm4+/− mouse to the well-established TP-ras0/+ murine melanoma progression model. After treatment with the carcinogen dimethylbenzanthracene (DMBA), TP-ras0/+ mice on the Mdm4+/− background developed fewer tumors with a delay in the age of onset of melanomas compared to TP-ras0/+ mice. Furthermore, we observed a dramatic decrease in tumor growth, lack of metastasis with increased survival of TP-ras0/+: Mdm4+/− mice. Thus, p53 effectively prevented the conversion of small benign tumors to malignant and metastatic melanoma. p53 activation in cultured primary melanocyte and melanoma cell lines using Nutlin-3, a specific Mdm2 antagonist, supported these findings. Moreover, global gene expression and network analysis of Nutlin-3-treated primary human melanocytes indicated that cell cycle regulation through the p21WAF1/CIP1 signaling network may be the key anti-melanomagenic activity of p53.
Terzian
Tamara
T
Department of Dermatology and Charles C Gates Center for Regenerative Medicine and Stem Cell Biology, UC Denver, Aurora, CO 80045, USA.
Torchia
Enrique C
EC
Dai
Daisy
D
Robinson
Steven E
SE
Murao
Kazutoshi
K
Stiegmann
Regan A
RA
Gonzalez
Victoria
V
Boyle
Glen M
GM
Powell
Marianne B
MB
Pollock
Pamela M
PM
Lozano
Guillermina
G
Robinson
William A
WA
Roop
Dennis R
DR
Box
Neil F
NF
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002453:Cell Cycle / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D002999:Clone Cells; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009506:Nevus / Q000378:metabolism / Q000473:pathology*; D010858:Pigmentation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D013194:Staining and Labeling; D016019:Survival Analysis; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D007093:Imidazoles; C461497:Mdm4 protein, mouse; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D015127:9,10-Dimethyl-1,2-benzanthracene; D044767:Ubiquitin-Protein Ligases