The Transcription Network Regulating Melanocyte Development and Melanoma

Abstract

The enormous variety of pigmentation phenotypes in nature reflects a series of remarkable events that begin in the neural crest and end with the manufacture and distribution of pigment by mature melanocytes located in the epidermis and hair follicles. While the origins of melanoblasts from multipotent precursors in the neural crest is striking in itself, yet more so is the fact that these pioneer melanoblasts manage to undertake and survive their long migration, and in doing so proliferate and maintain their identity before ultimately arriving at their destination and undergoing differentiation. With the application of the powerful combination of genetics and molecular and cell biology the mystery surrounding the genesis of the melanocyte lineage is slowly being unravelled. At its heart is the powerful alliance between signal transduction and transcription that coordinates the program of gene expression that confers on a cell its identity, provides its passport for migration, and instructs it in the arts of survival and timely reproduction. The realization that the proliferation and migration of melanoblasts during development resembles closely the proliferation and metastasis of melanoma, a highly dangerous and increasingly common cancer, serves to highlight the value of the melanocyte system as a model for addressing key issues of general significance in both development and cancer.

Effects on proliferation and melanogenesis by inhibition of mutant BRAF and expression of wild‐type INK4A in melanoma cells

“…19,36,37 MITF expression and activity are regulated by the ERK signaling pathway. Consistently, we found that MITF is increased in 624Mel cells expressing mutant BRAF RNAi (Fig.…”

“…[49][50][51] However, phosphorylation of these residues by the ERK signaling pathway has also been linked to an increase in MITF transcription activity through promoting its interaction with CBP and target DNA. 37 Clearly, much more needs to be done to understand how MITF is regulated by mutant BRAF in melanoma cells, including effects on MITF expression, phosphorylation, stability, protein-protein interaction, DNA binding and transcription activities.…”

Evolution of danio pigment pattern development

“…Besides their interest to evolutionary biologists, pigment patterns have long been a popular system for geneticists, developmental biologists, and mathematical modelers, who have exploited these patterns to study the emergence of biological form (Murray, 1989;Barsh, 1996;Quigley and Parichy, 2002;Dupin and Le Douarin, 2003;Vance and Goding, 2004;Parichy et al, 2006). Not only is this mostly two-dimensional trait easily analyzed even in the living animal, but the cells comprising a pigment pattern are of particular interest because of their neural crest origin.…”

Isolation and Characterization of Neural Crest Stem Cells Derived From In Vitro–Differentiated Human Embryonic Stem Cells

“…Given the diversity of its progeny, it is not surprising that disruption of the neural crest adversely affects human development and several complex human disorders such as DiGeorge, Waardenburg and Apert syndromes, neurofibromatosis, and Hirschsprung's disease arise because of aberrations in neural crest development [2,3]. In addition, several aggressive malignancies including malignant melanoma, neuroblastoma, and peripheral primitive neuroectodermal tumors-also known as Ewing sarcoma family tumors-have been proposed to arise because of genetic mutations in neural crest-derived cells [2,[4][5][6][7]. Thus, elucidation of human neural crest development and the mechanisms by which it is disrupted in human disease has the potential to profoundly impact our understanding of disease pathogenesis and, ultimately, afford opportunities for novel therapeutic interventions.…”