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The MC1R protein palmitoylation in melanoma development

MC1R 蛋白棕榈酰化在黑色素瘤发展中的作用

基本信息

批准号：
9788312
负责人：
Andrew W Taylor
金额：
$ 36.03万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-19 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788312
关键词：
Address Affect Animal Model Biological Biological Models Biology Cell Cycle Arrest Cells Centromere Clinical DNA Repair Defect Development Freckles G-Protein-Coupled Receptors Hair Hair Color Head In Vitro Incidence Individual Malignant - descriptor Mediating Melanins Melanocortin 1 Receptor Modification Molecular Mus Nature Outcome Study Oxidation-Reduction PTEN protein Patients Phenotype Physiological Pigmentation physiologic function Play Population Predisposition Preventive Process Proteins Receptor Gene Receptor Signaling Regulation Reporting Risk Role Skin Specific qualifier value Therapeutic Therapeutic Intervention Transferase Transgenic Mice Transgenic Organisms Tumor Suppressor Proteins UV Radiation Exposure UV induced UV-induced melanoma UVB induced Ultraviolet Rays Variant Work albino mouse alpha-Melanocyte stimulating hormone clinically relevant high risk in vivo in vivo Model insight loss of function loss of function mutation melanocyte melanoma microphthalmia-associated transcription factor mouse model new therapeutic target novel novel strategies palmitoylation premature prevent protein protein interaction receptor senescence tumor ultraviolet

项目摘要

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.

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激活的关键发信号。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。