A picture of Mitf in melanoma immortality

Goding, Colin R.

doi:10.1038/onc.2010.641

Cited by 63 publications

(72 citation statements)

References 10 publications

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“…GO term analysis [76,77] revealed that the subset of genes associated with both TFAP2A and MITF peaks are enriched for the terms “melanosome” and “pigment granule” (p = 9.08E-07), as well as “DNA repair” (p = 5.98E-08), “mitotic cell cycle process” (p = 5.59E-09), “regulation of cell proliferation” (p = 2.40E-03), and “regulation of cell differentiation” (p = 2.60E-03) (all p-values Bonferroni corrected, S9 Table). This supports a regulatory role for TFAP2A not only in differentiation, but across other categories of genes proposed to be regulated by MITF in melanocytes and melanoma, as with the MITF rheostat [22]. …”

Section: Resultssupporting

confidence: 59%

“…Because mice with loss-of-function mutations in Mitf lack melanocytes, and ectopic expression of MITF activates expression of melanin synthesis genes in heterologous cell types, MITF is considered a “master regulator” of melanocyte development [19–21]. MITF activity has also been described as a rheostat that regulates melanoma phenotype by driving senescence at low levels, an invasive phenotype at mid-levels, and melanocyte proliferation and differentiation at higher levels [22]. Continued exploration of the GRNs controlling melanocyte differentiation will add to the value of the melanocyte as a model cell type, and may also guide the design of differentiation-promoting therapies in melanoma.…”

Section: Introductionmentioning

confidence: 99%

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TFAP2 paralogs regulate melanocyte differentiation in parallel with MITF

et al. 2017

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Mutations in the gene encoding transcription factor TFAP2A result in pigmentation anomalies in model organisms and premature hair graying in humans. However, the pleiotropic functions of TFAP2A and its redundantly-acting paralogs have made the precise contribution of TFAP2-type activity to melanocyte differentiation unclear. Defining this contribution may help to explain why TFAP2A expression is reduced in advanced-stage melanoma compared to benign nevi. To identify genes with TFAP2A-dependent expression in melanocytes, we profile zebrafish tissue and mouse melanocytes deficient in Tfap2a, and find that expression of a small subset of genes underlying pigmentation phenotypes is TFAP2A-dependent, including Dct, Mc1r, Mlph, and Pmel. We then conduct TFAP2A ChIP-seq in mouse and human melanocytes and find that a much larger subset of pigmentation genes is associated with active regulatory elements bound by TFAP2A. These elements are also frequently bound by MITF, which is considered the “master regulator” of melanocyte development. For example, the promoter of TRPM1 is bound by both TFAP2A and MITF, and we show that the activity of a minimal TRPM1 promoter is lost upon deletion of the TFAP2A binding sites. However, the expression of Trpm1 is not TFAP2A-dependent, implying that additional TFAP2 paralogs function redundantly to drive melanocyte differentiation, which is consistent with previous results from zebrafish. Paralogs Tfap2a and Tfap2b are both expressed in mouse melanocytes, and we show that mouse embryos with Wnt1-Cre-mediated deletion of Tfap2a and Tfap2b in the neural crest almost completely lack melanocytes but retain neural crest-derived sensory ganglia. These results suggest that TFAP2 paralogs, like MITF, are also necessary for induction of the melanocyte lineage. Finally, we observe a genetic interaction between tfap2a and mitfa in zebrafish, but find that artificially elevating expression of tfap2a does not increase levels of melanin in mitfa hypomorphic or loss-of-function mutants. Collectively, these results show that TFAP2 paralogs, operating alongside lineage-specific transcription factors such as MITF, directly regulate effectors of terminal differentiation in melanocytes. In addition, they suggest that TFAP2A activity, like MITF activity, has the potential to modulate the phenotype of melanoma cells.

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Section: Resultssupporting

confidence: 59%

Section: Introductionmentioning

confidence: 99%

TFAP2 paralogs regulate melanocyte differentiation in parallel with MITF

et al. 2017

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“…A key determinant of melanoma differentiation sub-population identity is conferred by the expression and activation of microphthalmia-associated transcription factor ( MITF ). In melanoma, the induction of MITF expression promotes expression of differentiation markers and the inhibition of invasion [35]. Differentiation markers MelanA ( MLANA ) (fold change: 37), Tyrosinase ( TYR) (fold change: 27), and MITF (fold change: 10) were up-regulated in the epithelial-like cells examined.…”

Section: Resultsmentioning

confidence: 99%

Thrombospondin 1 promotes an aggressive phenotype through epithelial-to-mesenchymal transition in human melanoma

et al. 2014

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Epithelial-to-mesenchymal transition (EMT), in which epithelial cells loose their polarity and become motile mesenchymal cells, is a determinant of melanoma metastasis. We compared gene expression signatures of mesenchymal-like melanoma cells with those of epithelial-like melanoma cells, and identified Thrombospondin 1 (THBS1) as highly up-regulated in the mesenchymal phenotype. This study investigated whether THBS1, a major physiological activator of transforming growth factor (TGF)-beta, is involved in melanoma EMT-like process. We sought to examine expression patterns in distinct melanoma phenotypes including invasive, de-differentiated, label-retaining and drug resistant populations that are putatively associated with an EMT-like process.Here we show that THBS1 expression and secretion was elevated in melanoma cells exhibiting invasive, drug resistant, label retaining and mesenchymal phenotypes and correlated with reduced expression of genes involved in pigmentation. Elevated THBS1 levels were detected in Vemurafenib resistant melanoma cells and inhibition of THBS1 led to significantly reduced chemoresistance in melanoma cells. Notably, siRNA-mediated silencing of THBS1 and neutralizing antibody to THBS1 reduced invasion in mesenchymal-like melanoma cells, while ectopic THBS1 expression in epithelial-like melanoma cells enhanced invasion. Furthermore, the loss of THBS1 inhibited in vivo motility of melanoma cells within the embryonic chicken neural tube. In addition, we found aberrant THBS1 protein expression in metastatic melanoma tumor biopsies. These results implicate a role for THBS1 in EMT, and hence THBS1 may serve as a novel target for strategies aimed at the treatment of melanoma invasion and drug resistance.

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“…MITF expression is governed by a variety of signals that ultimately produce an expression level that dictates cellular phenotype. In this way, MITF is proposed to act as a rheostat (41,56,57). Specifically, high levels of MITF promote cell-cycle arrest and terminal differentiation, whereas lower expression levels stimulate proliferation.…”

Section: Discussionmentioning

confidence: 99%