Why red-haired individuals are so prone to developing melanoma

 描述(申请人提供)：黑色素瘤是一种高度侵袭性的癌症，发病率呈惊人的上升趋势。黑色素瘤生物学中的一个主要问题是，为什么红头发的人患黑色素瘤的风险很高。黑素皮质素-1受体(MC1R)基因的变异，编码一种由α-黑素细胞刺激素(a-MSH)激活的三聚体G蛋白偶联受体，经常与红色或金发、白皙皮肤、雀斑和皮肤对紫外线(UV)敏感有关，几种(RHC-变异)也与 会增加患黑色素瘤的风险。这些变异中的几个与黑色素瘤风险增加有关。然而，并不是所有这些关联都归因于表型，这表明一些变异影响黑色素瘤的风险独立于表型。利用体内模型系统，我们最近报道了一些MC1R突变与紫外线协同诱导黑色素瘤，而不依赖于它们对色素沉着的影响。因此，准确了解MC1R RHC变异体如何不同地影响黑色素瘤生物学是一个关键问题。重要的是，我们最近还报道了紫外线照射触发了MC1R与PTEN的相互作用和降解，导致黑素细胞中PI3K信号驱动的衰老增加，但在BRAF突变的黑色素瘤中却绕过了衰老。重要的是，WT MC1R而不是红发相关的MC1R RHC变异体可以与PTEN相互作用。在这里，我们将使用新产生的MC1R条件性RHC变异小鼠模型来剖析MC1R在体内启动黑色素瘤过程中的肿瘤抑制功能，特别是它在通过PTEN降解控制PI3K信号转导中的作用。我们还将进行所需的深入机制研究，以确定潜在的治疗干预目标。最后，我们将在MC1R/PTEN相互作用的深入分子机制(S)的指导下，开发新的黑色素瘤预防和治疗策略。我们建议的研究将确定MC1R在抑制黑色素瘤起始方面的细胞内分子靶点，旨在确定黑色素瘤预防和治疗干预的新策略。

 DESCRIPTION (provided by applicant): Melanoma is a highly aggressive cancer with an alarmingly increasing incidence. A major question in melanoma biology is why are red-haired individuals at a high risk of developing melanoma. Variants in the melanocortin-1-receptor (MC1R) gene, encoding a trimeric G protein- coupled receptor activated by a-melanocyte-stimulating hormone (a-MSH), are frequently associated with red or blonde hair, fair skin, freckling and skin sensitivity to ultraviolet (UV) light, and several (RHC-variants) also associate with increased melanoma risk. Several of these variants are associated with increased melanoma risk. However, not all of these associations have been attributed to phenotype, suggesting that some variants affect melanoma risk independent of phenotype. Using an in vivo model system, we recently reported that some MC1R mutations synergize with UV to induce melanoma independently of their effects on pigmentation. Understanding precisely how MC1R RHC-variants differentially affect melanoma biology is therefore a key issue. Importantly, we also reported recently that UV irradiation triggered MC1R-interaction with and degradation of PTEN, leading to increased PI3K- signalling-driven senescence in melanocytes, but senescence bypass in BRaf mutant melanoma. Importantly, WT MC1R but not red-hair associated MC1R RHC-variants could interact with PTEN. Here, we will use newly generated MC1R conditional RHC-variant mouse models to dissect the tumor suppressive functions of MC1R in melanoma initiation in vivo and specifically its role in controlling PI3K signaling via PTEN degradation. We will also undertake the in-depth mechanistic studies required to identify potential targets for therapeutic intervention. Finally, we will develop novel preventive and therapeutic strategies in melanoma guided by the in-depth molecular mechanism(s) in the MC1R/PTEN interaction. Our proposed studies will identify intracellular molecular targets of MC1R in suppressing melanoma initiation that are directed towards identifying novel strategies for melanoma prevention and therapeutic intervention.