Control of melanocyte differentiation by a MITF–PDE4D3 homeostatic circuit

Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Massachusetts 02114, USA.
Genes & development (Impact Factor: 10.8). 10/2010; 24(20):2276-81. DOI: 10.1101/gad.1937710
Source: PubMed


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.

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    • "MITF is regulated by a variety of transcription factors including itself (Levy et al., 2006) and mediates a variety of cellular programs via downstream gene targets (Beuret et al., 2011; Cheli et al., 2010; Hoek et al., 2008b; Levy and Fisher, 2011; Strub et al., 2011). Within melanocytes, MITF is involved in lineage-specific and ubiquitous cellular programs such as differentiation (TYR, TYRP1, DCT, MLANA, PDE4DE) (Cheli et al., 2010; Khaled et al. 2010; Levy et al., 2006), cellular response mechanisms (Aoki and Moro, 2002; Hornyak et al., 2009 "
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    ABSTRACT: Studies examining intratumor heterogeneity have indicated that several cancer types, including melanoma, can display phenotypic plasticity, corresponding to their capacity to undergo transient reversible cellular changes. Conceptual models constructed to explain the process of cancer propagation differ in their treatment of intratumor heterogeneity. Recent observations of reversible phenotypic heterogeneity in melanoma have led to the proposal of a novel 'phenotypic plasticity' model of cancer propagation. Microphthalmia-associated transcription factor (MITF), the melanocyte 'lineage-specific' transcription factor, has emerged as one of the central players in melanoma phenotypic plasticity. Here we discuss the conceptual models suggested to explain the relations between MITF and melanoma plasticity, in addition to the complex regulatory roles that MITF plays in melanocytes and melanoma development. Finally, we provide an in-depth literature survey of microRNAs (miRNAs) involved in MITF activity, melanoma propagation and metastasis, in addition to their potential use as agents of personalized therapy.
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    • "We reported that topical application of the adenylate cylase activating drug forskolin restored melanotic pigmentation in an animal model of the fair-skinned human (Fig. 10) and that this " sunless tanning " was potently protective against UV damage and carcinogenesis of the skin (D'Orazio et al., 2006). More recently, Khaled and coworkers showed that a similar UV-protected phenotype could be induced not by induction of cAMP generation, but rather by pharmacologic interference with clearance of cAMP by topical application of a phosphodiesterase inhibitor (Khaled et al., 2010). Small molecule-based approaches of cAMP manipulation may offer a critical advantage over MSH peptide mimetics in that fair-skinned, UV-sensitive persons most at risk of melanoma are frequently defective in MC1R signaling ability, and thus would not be expected to generate a brisk cAMP response upon MSH peptide binding. "

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