Activation of the Mitf promoter by lipid‐stimulated activation of p38‐stress signalling to CREB

Abstract

The microphthalmia-associated transcription factor Mitf plays a critical role in regulating many aspects of melanocyte biology. It is required for melanoblast and postnatal melanocyte survival, regulates proliferation, and activates genes associated with differentiation such as tyrosinase and related genes involved in melanogenesis. Identifying the signals that regulate Mitf expression is crucial if we are to understand how cells of the melanocyte lineage respond to environmental cues. Here we show that the Mitf promoter is induced by lipid signalling via the p38 stress-activated kinase pathway that is also activated by a wide range of receptors as well as UV irradiation. Signalling via p38 leads to increased phosphorylation and activation of cyclic adenosine monophosphate response element-binding (CREB) that binds and activates the Mitf promoter via the cyclic adenosine monophosphate (cAMP) response element. Moreover, we also show that activation of p38 mediated by lipids is potentiated by inhibition of the PI3kinase pathway but not by inhibition of protein kinase A (PKA). The results identify a mechanism in which stress signalling via p38 leads to activation of CREB, enhanced Mitf expression and consequently increased tyrosinase expression. The results are relevant for the regulation of melanocytes by Mitf, but also raise the possibility that lipid mediated activation of p38 signalling may represent a potential therapy for vitiligo.

Bone morphogenetic proteins differentially regulate pigmentation in human skin cells

“…We also found that BMP6 induced MITF and TYR mRNA expression in MC, was blocked by the p38MAPK inhibitor, validating our view that p38MAPK plays an important role in BMP6-induced melanogenesis, and concurs with previous reports that BMPs stimulate MITF and TYR protein expression in chick embryo retinal pigment epithelium (Müller et al, 2007). Stress signalling, mediated via p38MAPK phosphorylation, is known to result in a rapid and persistent phosphorylation of Ser307 of MITF, which we and others have shown to be responsible for the transcription of genes involved in MC differentiation, proliferation and survival (Mansky et al, 2002;Vance and Goding, 2004;Saha et al, 2006). Furthermore, UVR-induced activation of stress-responsive p38MAPK can also lead to the phosphorylation of the ubiquitous bHLH-LZ transcription factor, USF-1, and like MITF this can bind and activate the TYR promoter in human MC (Galibert et al, 2001).…”

Integration of ChIP-seq and machine learning reveals enhancers and a predictive regulatory sequence vocabulary in melanocytes

“…It is also notable that one of the top 6-mers (ranked fourth) is predicted to bind PAX3, a key regulator of melanocyte differentiation (Lang et al 2005) which can cause Waardenburg syndrome type 1 and type 3 when mutated (OMIM:193500 and OMIM:148820, respectively). In addition, CREB1, SOX5, and RUNX-family TFs (predicted to bind 6-mers ranked fifth, eighth, and ninth, respectively) have been shown to play roles in regulating gene expression in melanocytes (Tada et al 2002;Raveh et al 2005;Saha et al 2006;Kingo et al 2008;Stolt et al 2008;Kanaykina et al 2010;Mizutani et al 2010).…”

Interferon-γ Attenuates 5-Hydroxytryptamine-Induced Melanogenesis in Primary Melanocyte

“…33) The activation of this pathway induced the phosphorylation of CREB, resulting in the expression of TYR, TRP-1, and DCT genes. 34) As the data showed in Fig. 1F, 5-HT treatment for 120 min induced CREB phosphorylation, while IFN-γ has no obvious effect on CREB phosphorylation.…”