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

紫外线照射、红发、痣和黑色素瘤之间的分子联系

基本信息

批准号：
9014144
负责人：
Rutao Cui
金额：
$ 37.52万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9014144
关键词：
AKT inhibition Address Affect Animal Model Biological Models Biology Bypass Cell Cycle Arrest Clinical Development Ectopic Expression Freckles Functional disorder G-Protein-Coupled Receptors Genetic Hair Hairy Nevus Human Incidence Individual Lead Lipids Malignant Neoplasms Mediating Melanins Melanocortin 1 Receptor Molecular Molecular Target Mouse Strains Mus Mutation Nevi and Melanomas Nevus Oncogenes Oncogenic Outcome Study PTEN gene Phenotype Phosphoric Monoester Hydrolases Phosphorylation Physiological Pigmentation physiologic function Population Preventive Intervention Production Protein phosphatase Proto-Oncogene Proteins c-akt Receptor Gene Reporting Risk Role Signal Pathway Signal Transduction Skin Specimen Testing Therapeutic Intervention Transgenic Mice Transgenic Organisms Tumor Suppressor Proteins UV Radiation Exposure UV induced UVB induced Ubiquitination Ultraviolet Rays Variant Work albino mouse alpha-Melanocyte stimulating hormone enzyme activity high risk in vivo in vivo Model insight loss of function loss of function mutation melanocyte melanoma mouse model mutant novel strategies overexpression premature prevent public health relevance receptor expression senescence targeted treatment therapeutic target trait tumor ubiquitin-protein ligase ultraviolet ultraviolet irradiation

项目摘要

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.

描述（由申请人提供）：黑色素瘤是一种高度侵袭性的癌症，其发病率正在惊人地增加。黑色素瘤生物学的一个主要问题是为什么红发个体患黑色素瘤的风险很高。黑皮质素-1-受体 (MC1R) 基因的变异体编码由 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) 敏感有关，并且一些（RHC 变异体）也与红色或金色头发、白皙皮肤、雀斑和皮肤对紫外线 (UV) 敏感有关。黑色素瘤风险增加。其中一些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，这表明某些变异影响黑色素瘤风险的因素与表型无关。我们最近使用体内模型系统报道，一些 MC1R 突变与紫外线协同作用，诱导黑色素瘤，而与它们对色素沉着的影响无关。因此，准确了解 MC1R RHC 变体如何对黑色素瘤生物学产生差异性影响是一个关键问题。重要的是，我们最近还报道，紫外线照射触发了 MC1R 与 PTEN 的相互作用和降解，导致黑色素细胞中 PI3K 信号驱动的衰老增加，但 BRaf 突变黑色素瘤中的衰老绕过。重要的是，WT MC1R 但不是红发相关 MC1R RHC 变体可以与 PTEN 相互作用。在这里，我们将使用新生成的 MC1R 条件性 RHC 变异小鼠模型来剖析 MC1R 在体内黑色素瘤起始中的肿瘤抑制功能，特别是其通过 PTEN 降解控制 PI3K 信号传导的作用。我们还将进行深入的机制研究，以确定潜在的靶点并确定 MC1R 的上游调节因子以进行治疗干预。我们提出的研究将确定 MC1R 抑制黑色素瘤发生的细胞内分子靶标，旨在确定黑色素瘤预防和治疗干预的新策略。