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p53 prevents progression of nevi to melanoma predominantly through cell cycle regulation
Author(s) -
Terzian Tamara,
Torchia Enrique C.,
Dai Daisy,
Robinson Steven E.,
Murao Kazutoshi,
Stiegmann Regan A.,
Gonzalez Victoria,
Boyle Glen M.,
Powell Marianne B.,
Pollock Pamela M.,
Lozano Guillermina,
Robinson William A.,
Roop Dennis R.,
Box Neil F.
Publication year - 2010
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/j.1755-148x.2010.00773.x
Subject(s) - melanoma , cancer research , melanocyte , biology , tumor progression , mdm2 , dmba , cell cycle , tumor suppressor gene , metastasis , cell growth , cancer , cell culture , carcinogenesis , genetics
Summary 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‐ras 0/+ murine melanoma progression model. After treatment with the carcinogen dimethylbenzanthracene (DMBA), TP‐ras 0/+ mice on the Mdm4 +/− background developed fewer tumors with a delay in the age of onset of melanomas compared to TP‐ras 0/+ mice. Furthermore, we observed a dramatic decrease in tumor growth, lack of metastasis with increased survival of TP‐ras 0/+ : 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 p21 WAF1/CIP1 signaling network may be the key anti‐melanomagenic activity of p53.