Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Massachusetts 02114, USA.
Genes Dev. 2010 Oct 15;24(20):2276-81. doi: 10.1101/gad.1937710.
Cyclic AMP (cAMP) is a ubiquitous second messenger that regulates a variety of biological processes. The magnitude and duration of cAMP expression are regulated by both production and hydrolysis. Melanocyte-stimulating hormone (MSH) plays a crucial role in pigment cell differentiation via cAMP-regulated expression of the master transcription factor MITF. We report the identification of phosphodiesterase 4D3 as a direct target of the MSH/cAMP/MITF pathway. This creates a negative feedback loop that induces refractoriness to chronic stimulation of the cAMP pathway in melanocytes. This homeostatic pathway highlights a potent mechanism controlling melanocyte differentiation that may be amenable to pharmacologic manipulation for skin cancer prevention.
环磷酸腺苷 (cAMP) 是一种普遍存在的第二信使,调节着多种生物过程。cAMP 的表达幅度和持续时间受到其产生和水解的调节。促黑激素 (MSH) 通过 cAMP 调节主转录因子 MITF 的表达,在色素细胞分化中发挥关键作用。我们报告了磷酸二酯酶 4D3 的鉴定,它是 MSH/cAMP/MITF 途径的直接靶标。这创建了一个负反馈回路,导致黑色素细胞对 cAMP 途径的慢性刺激产生抗性。这种体内平衡途径突出了一种控制黑色素细胞分化的有效机制,可能适合用于皮肤癌预防的药物干预。