The MC1R protein palmitoylation in melanoma development

摘要 黑色素瘤生物学中与临床相关的一个主要问题是，为什么红发个体处于 患黑色素瘤的风险很高。黑皮质素-1-受体（MC 1 R）基因的变体，编码一种 三聚体G蛋白偶联受体由α-黑素细胞刺激激素（α-MSH）激活， 经常与红色或金色头发、白皙皮肤、雀斑和皮肤对紫外线（UV）敏感有关 此外，MC 1 R的几种红色发色变体（RHC变体）也与增加的 黑素瘤风险。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，与表型无关。使用体内模型系统，我们 报道，一些MC 1 R RHC-变体与UV协同作用以独立于它们的功能诱导黑素瘤。 对色素沉着的影响准确了解MC 1 R RHC变体如何差异性影响黑色素瘤 因此，生物学是连接红头发和黑色素瘤易感性的关键问题。最近，我们进一步 报道了一种新的MC 1 R蛋白修饰，棕榈酰化，这是MC 1 R激活的关键 信号我们还发现了α-MSH/MC 1 R在着丝粒完整性中的一个新的关键作用。在此，我们将进一步 研究MC 1 R蛋白棕榈酰化的调节因子和机制及其在 保护着丝粒的完整性，这可能有助于确定新的潜在的治疗策略， 黑色素瘤的干预。此外，我们将使用新产生的MC 1 R条件性RHC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， 在保护着丝粒完整性和确定MC 1 R蛋白棕榈酰化在UV诱导的 黑色素瘤发展。鉴于MC 1 R变异体之间的联系，红头发/白皙皮肤表型和 黑色素瘤的发展，这些研究将有助于回答一个与临床相关的问题“为什么红头发 个体是如此容易发展为黑色素瘤”，并将导致新的预防措施的确定， 以及黑色素瘤，特别是红头发黑色素瘤的治疗策略。

Abstract A major question in melanoma biology with clinical relevance is why red-haired individuals are 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 red hair color variants (RHC-variants) of MC1R also associate 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 reported that some MC1R RHC-variants 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 to connect red-heads and melanoma susceptibility. Recently, we further reported a novel modification of MC1R protein, palmitoylation, which is crucial in the activation of MC1R signaling. We also found a new critical role of α-MSH/MC1R in centromere integrity. Herein, we will further investigate the regulators and mechanisms underlying MC1R protein palmitoylation and its role in protecting centromere integrity, which could help identify new potential strategies for therapeutic intervention of melanoma. In addition, we will use newly generated MC1R conditional RHC-variant mouse models to dissect the tumor suppressive functions of MC1R in melanoma initiation in vivo, specify its role in protecting centromere integrity and determine the role of MC1R protein palmitoylation in UV-induced melanoma development. Given the connection among MC1R variants, red hair/fair skin phenotype and melanoma development, these studies will help answer a question with clinical relevance “why red-haired individuals are so prone to developing melanoma” and will lead to the identification of novel preventive and therapeutic strategies for melanoma, especially melanomas in red-heads.