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Why red-haired individuals are so prone to developing melanoma

为什么红头发的人这么容易患黑色素瘤

基本信息

批准号：
9282700
负责人：
Rutao Cui
金额：
$ 37.45万
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：
2015-07-15 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9282700
关键词：
AKT inhibition Address Affect Animal Model Biological Models Biology Bypass Cell Aging Cell Cycle Arrest Clinical Cyclic AMP DNA Repair Development Freckles Functional disorder G-Protein-Coupled Receptors Genetic Hair Impairment Incidence Individual Lead Lipids Malignant Neoplasms Mediating Melanins Melanocortin 1 Receptor Molecular Molecular Target Mouse Strains Mus Mutation Nevus Oncogenic Outcome Study PI3K/AKT PTEN gene Phenotype Phosphoric Monoester Hydrolases Phosphorylation Inhibition Physiological Pigmentation physiologic function Pigments Population Preventive Preventive Intervention Production Protein phosphatase Proto-Oncogene Proteins c-akt Receptor Gene Reporting Risk Role Sampling Signal Pathway Signal Transduction Skin Testing Therapeutic Therapeutic Intervention Transgenic Mice Transgenic Organisms Tumor Suppressor Proteins UV Radiation Exposure UV induced UVB induced Ultraviolet Rays Variant Work albino mouse alpha-Melanocyte stimulating hormone analog carcinogenesis enzyme activity high risk in vivo in vivo Model inhibitor/antagonist insight loss of function loss of function mutation melanocyte melanoma mouse model mutant novel novel strategies premature prevent public health relevance 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 a-melanocyte-stimulating hormone (a-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 for therapeutic intervention. Finally, we will develop novel preventive and therapeutic strategies in melanoma guided by the in-depth molecular mechanism(s) in the MC1R/PTEN interaction. 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，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发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，经常与红色或金色头发、白皙皮肤、雀斑和皮肤对紫外线（UV）光的敏感性相关，并且几种（RHC变体）也与皮肤对紫外线（UV）光的敏感性相关。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，我们最近还报道了UV照射触发了MC 1 R与PTEN的相互作用和PTEN的降解，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，以确定治疗干预的潜在目标。最后，我们将在MC 1 R/PTEN相互作用的深入分子机制的指导下开发新的黑色素瘤预防和治疗策略。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。