Molecular connections among UV exposure, red hair, nevi and melanoma

 描述（由申请人提供）：黑色素瘤是一种高度侵袭性的癌症，发病率惊人地增加。黑色素瘤生物学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。黑皮质素-1-受体（MC 1 R）基因的变异体，编码一种由α-黑素细胞刺激激素（α-MSH）激活的三聚体G蛋白偶联受体，通常与红色或金色头发、白皙皮肤、雀斑和皮肤对紫外线（UV）光的敏感性有关，几种（RHC变异体）也与 黑色素瘤风险增加其中几种变异与黑色素瘤风险增加有关。然而，并非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风险独立于表型。使用体内模型系统，我们最近报道，一些MC 1 R突变协同UV诱导黑色素瘤独立于其对色素沉着的影响。因此，准确了解MC 1 R RHC变体如何差异性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，紫外线照射引发MC 1 R与PTEN的相互作用和降解，导致黑素细胞中PI 3 K信号转导驱动的衰老增加，但BRaf突变型黑色素瘤中的衰老旁路。重要的是，WT MC 1 R而不是红发相关的MC 1 R RHC变体可以与PTEN相互作用。在这里，我们将使用新生成的MC 1 R条件性MHC变异小鼠模型来剖析MC 1 R在体内黑色素瘤起始中的肿瘤抑制功能，特别是其在通过PTEN降解控制PI 3 K信号传导中的作用。我们还将进行深入的机制研究，以确定潜在的目标，并确定MC 1 R的上游调节因子进行治疗干预。我们提出的研究将确定MC 1 R在抑制黑色素瘤启动中的细胞内分子靶点，这些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 α-melanocyte-stimulating hormone (α-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 and identify upstream regulators of MC1R for therapeutic intervention. 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.