p53 prevents progression of nevi to melanoma predominantly through cell cycle regulation

Abstract

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.

Alpha-Melanocyte–Stimulating Hormone Suppresses Oxidative Stress through a p53-Mediated Signaling Pathway in Human Melanocytes

“…5C), the major enzymes involved in BER (33,34). Our results are in agreement with other reports that accumulation of p53 in melanocytes or melanoma cells induces genes that regulate cell-cycle arrest rather than apoptosis and increases the expression of OGG1 in human fibroblasts (35,36).…”

Restoring the tumour suppressive function of p53 as a parallel strategy in melanoma therapy

“…The importance of p53 in suppressing melanoma growth is supported by the rapid proliferation of BRAFV600E containing melanocytes on loss of p53 function [36]. Also, p53 prevents progression of naevi to melanoma in a transgenic mouse model [37]. In agreement with this Avery-Kiejda et al observed abnormal expression of p53 downstream target genes, in particular pro-apoptotic genes including Bax and PIG3 in melanoma [38].…”

Heat stress: A risk factor for skin carcinogenesis

“…As previously mentioned, this protein is involved in maintaining genomic stability, and can enforce a G1 cell cycle arrest or induce apoptosis in response to cellular stresses (Harris and Levine, 2005). As outlined above, cell cycle arrest at the G1 phase is very important as it allows for cellular repair pathways to remove damage before DNA synthesis and cell mitosis can begin (Terzian et al, 2010). Conversely, p53-induced apoptosis helps eliminate potential tumour cell progenitors.…”