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，为什么红发患者处于 患黑色素瘤的风险很高。黑素皮质素-1受体(MC1R)基因的变体，编码 由α-黑素细胞刺激素(α-MSH)激活的三聚体G蛋白偶联受体 经常与红色或金色头发、白皙皮肤、雀斑和皮肤对紫外线敏感有关 光，以及MC1R的几个红色头发变种(RHC变种)也与增加 黑色素瘤风险。然而，并不是所有这些关联都归因于表型，这表明 某些变异对黑色素瘤风险的影响与表型无关。使用活体模型系统，我们 据报道，一些MC1R RHC变异体与紫外线协同诱导黑色素瘤的作用不依赖于其自身 对色素沉着的影响。准确了解MC1R RHC变异对黑色素瘤的差异影响 因此，生物学是将红发与黑色素瘤易感性联系起来的关键问题。最近，我们进一步 报道了对MC1R蛋白的一种新的修饰，即棕榈酰化，它在MC1R的激活中起关键作用 发信号。我们还发现了α-msh/mc1R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MC1R蛋白棕榈酰化的调节和机制及其在体内的作用 保护着丝粒完整性，这可能有助于确定新的潜在治疗策略 黑色素瘤的干预。此外，我们将使用新生成的MC1R条件性RHC变异小鼠 分析MC1R在体内黑色素瘤发生中的肿瘤抑制功能的模型，明确其作用 在保护着丝粒完整性和确定MC1R蛋白棕榈酰化在紫外线诱导中的作用 黑色素瘤的发展。考虑到MC1R变异、红发/白皙皮肤表型和 关于黑色素瘤的发展，这些研究将有助于回答一个与临床相关的问题：为什么是红发 个人很容易患上黑色素瘤“，这将导致新的预防措施的确定 以及黑色素瘤的治疗策略，特别是红发黑色素瘤。

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.