Laurette Patrick, Koludrovic Dana, Coassolo Sebastien, Davidson Irwin
Biol Aujourdhui. 2016;210(4):283-295. doi: 10.1051/jbio/2016028. Epub 2017 Mar 22.
Malignant melanoma is a highly aggressive cancer with a propensity for early metastasis. Melanocyte transformation results predominantly from oncogenic mutations in BRAF, NRAS or NF1 leading to constitutive activation of the MAP kinase pathway driving cell proliferation and second site mutations such as loss of CDKN1A, or PTEN or activating mutations in the beta-catenin pathway that allow escape from oncogene induced senescence. Nevertheless, irrespective of the nature of the driver mutations, melanoma cell physiology is strongly regulated by transcription factors and epigenetic mechanisms. MITF (Microphthalmia-associated Transcription Factor) and SOX10 are two major transcription factors that regulate both normal melanocyte and melanoma cell physiology. Using a combination of mouse genetics, biochemistry and high throughput genomics we have identified cofactors for MITF and addressed the mechanisms by which MITF, SOX10 and their cofactors regulate gene expression in melanocytes and melanoma.
恶性黑色素瘤是一种侵袭性很强的癌症，易于早期转移。黑色素细胞转化主要源于BRAF、NRAS或NF1中的致癌突变，导致MAP激酶途径的组成性激活，驱动细胞增殖以及诸如CDKN1A缺失、PTEN缺失或β-连环蛋白途径中的激活突变等二次位点突变，从而使细胞逃避癌基因诱导的衰老。然而，无论驱动突变的性质如何，黑色素瘤细胞生理学都受到转录因子和表观遗传机制的强烈调控。MITF（小眼相关转录因子）和SOX10是两种主要的转录因子，它们调节正常黑色素细胞和黑色素瘤细胞的生理学。通过结合小鼠遗传学、生物化学和高通量基因组学，我们已经确定了MITF的辅因子，并探讨了MITF、SOX10及其辅因子调节黑色素细胞和黑色素瘤中基因表达的机制。
