Activation of the Mitf promoter by lipid-stimulated activation of p38-stress signalling to CREB
Activation of the Mitf promoter by lipid-stimulated activation of p38-stress signalling to CREB
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DOI：
10.1111/j.1600-0749.2006.00348.x
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发表时间：
2006-12-01
期刊：
影响因子：
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通讯作者：
Bhadra, Ranjan
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文献类型：
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作者：
Saha, Bidisha;Singh, Suman Kumar;Bhadra, Ranjan
小眼炎相关转录因子MITF在黑素细胞生物学的许多方面起着重要的调节作用。它是黑素母细胞和出生后黑素细胞生存所必需的，调节增殖，并激活与分化相关的基因，如酪氨酸酶和参与黑素生成的相关基因。如果我们想要了解黑素细胞系的细胞如何对环境提示做出反应，识别调节MITF表达的信号是至关重要的。在这里，我们表明，MITF启动子是由脂类信号诱导的，通过p38应激激活激酶途径，该途径也被广泛的受体激活以及紫外线照射。通过p38的信号转导导致环一磷酸腺苷反应元件结合(CREB)的磷酸化和激活增加，CREB通过环一磷酸腺苷(CAMP)反应元件结合和激活MITF启动子。此外，我们还表明，脂类介导的p38的激活是通过抑制PI3K途径而不是通过抑制蛋白激酶A(PKA)来增强的。这些结果确定了一种机制，即通过p38的胁迫信号导致CREB激活，MITF表达增强，从而增加酪氨酸酶的表达。这些结果与MITF对黑素细胞的调节有关，但也提高了脂质介导的p38信号激活可能是白癜风的潜在治疗方法的可能性。
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.