Defining a New Role for Alpha-MSH: Antioxidant in UVB-Irradiated Melanocytes

定义 Alpha-MSH 的新作用：UVB 照射的黑素细胞中的抗氧化剂

• 批准号: 8106444
• 负责人: Ana Luisa Kadekaro
• 金额: $ 19.43万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-07 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8106444
• 关键词: 8-Oxoguanine DNA Glycosylase; 8-oxo-7,8-dihydrodeoxyguanine; Address; Advocate; Antioxidants; Area; Awareness; BRAF gene; Binding; CDKN2A gene; Cell Nucleus; Clinical; Cutaneous Melanoma; Cyclic AMP; Cyclobutanes; Cytoplasm; DNA Damage; DNA Repair; DNA photoproducts; DNA repair protein; Data; Disease; Enzymes; Etiology; Exhibits; Ferritin; Free Radicals; Generations; Genes; Glutathione S-Transferase; Homeostasis; Human; Hydrogen Peroxide; Incidence; Individual; Knowledge; Lead; MDM2 gene; Malignant - descriptor; Melanocortin 1 Receptor; Melanocyte stimulating hormone; Melanogenesis; Mitogen-Activated Protein Kinase Kinases; Molecular; Mutation; NAD(P)H dehydrogenase (quinone) 1, human; NF-E2-related factor 2; Nuclear Translocation; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Phase; Phosphorylation; Play; Predisposition; Prevention; Prevention strategy; Proliferating Cell Nuclear Antigen; Proteins; Public Health; Reactive Oxygen Species; Refractory; Response Elements; Role; Serine; Signal Pathway; Skin; Skin Cancer; Skin tanning; Solar Energy; Squamous cell carcinoma; Sun Exposure; Susceptibility Gene; TP53 gene; Testing; The Sun; Transcend; Tumor-Derived; UV induced; Ultraviolet B Radiation; Ultraviolet Rays; alpha-Melanocyte stimulating hormone; base; carcinogenesis; catalase; dimer; environmental stressor; fight against; heme oxygenase-1; inhibitor/antagonist; keratinocyte; loss of function; melanocyte; melanoma; novel; nuclear factor-erythroid 2; nutlin 3; oxidative DNA damage; paracrine; photoprotection; pifithrin; prevent; programs; promoter; protein kinase A kinase; public health relevance; repaired; replication factor A; response; small hairpin RNA; transcription factor; tumor; ultraviolet irradiation

DESCRIPTION (provided by applicant): Cutaneous malignant melanoma incidence continues to rise, and prevention is still the best way to fight against the disease, yet efficient prevention strategies are hindered by the lack of knowledge of the mechanisms involved in melanomagenesis. The carcinogenic pathways that lead to the malignant transformation of epidermal melanocytes (hMCs) to melanoma seem to differ from those that lead to the transformation of keratinocytes in basal or squamous cell carcinoma tumors. While keratinocyte-derived tumors commonly present typical "UV signature" mutations, particularly in the TP53 gene, such mutations are rare in melanoma tumors. Although there is compelling evidence for the role of ultraviolet radiation (UVR), for at least a subset of melanoma tumors that arise in sun exposed areas of the body, DNA photoproducts that are directly induced by UVR, do not seem to be the main cause for the genetic alterations in melanoma-associated genes. Mutations in p16 and BRAF genes, which are suggested to be induced by oxidative stress, underscore the central role of UVR-induced oxidative stress in hMC malignant transformation to melanoma. Studies addressing the mechanisms that counteract UVR-induced oxidative stress in hMCs, have important clinical and public health implications since they should provide novel means for melanoma prevention strategies. The objective of this proposal is to test the central hypothesis that a-melanocyte stimulating hormone (a-MSH), an important paracrine factor that is required for melanogenic (i.e. tanning) response to solar radiation, protects melanocytes from the carcinogenic effect of UVR by reducing the generation of reactive oxygen species (ROS), increasing the expression and/or activity of antioxidant proteins, and enhancing the repair of oxidative DNA damage. We propose two specific aims: 1) to test the hypothesis that a-MSH exerts its antioxidant effects by modulating the activity of the transcription factor NF-E2-related factor (Nrf-2) and 2) to test the hypothesis that accumulation and transcriptional activity of p53 are necessary for a-MSH reduction of oxidative DNA damage. This proposal will define a new role for a-MSH in UVR photoprotection of hMCs that transcends its classically known effect as an inducer of melanogenesis, and includes reduction of UV-induced oxidative DNA damage, as a possible primary protective mechanism. Public Health Relevance: The incidence of cutaneous malignant melanoma, the deadliest form of skin cancer, continues to rise. The objective of this study is to demonstrate that a-melanocyte stimulating hormone (a-MSH), an important factor for tanning response in the skin, protects melanocytes from the carcinogenic effect of UV by reducing the burden caused by free radicals. In this study, we are proposing to investigate the molecular pathways by which a-MSH counteracts the UV-induced oxidative stress in human melanocytes, and thus prevents their malignant transformation to melanoma.

描述（由申请人提供）：皮肤恶性黑色素瘤的发病率持续上升，预防仍然是对抗该疾病的最佳方法，但由于缺乏对黑色素瘤发生机制的了解，有效的预防策略受到阻碍。导致表皮黑素细胞（hMC）恶性转化为黑色素瘤的致癌途径似乎与导致基底细胞或鳞状细胞癌肿瘤中角质形成细胞转化的致癌途径不同。虽然角质形成细胞来源的肿瘤通常存在典型的“UV特征”突变，特别是在TP 53基因中，但这种突变在黑色素瘤肿瘤中很少见。尽管有令人信服的证据表明紫外线辐射（UVR）的作用，但对于至少一部分出现在身体暴露于阳光的区域的黑色素瘤肿瘤，由UVR直接诱导的DNA光产物似乎不是黑色素瘤相关基因遗传改变的主要原因。p16和BRAF基因的突变，这被认为是由氧化应激引起的，强调了UVR诱导的氧化应激在人MC恶性转化为黑色素瘤中的核心作用。研究解决机制，抵消紫外线诱导的氧化应激hMCs，具有重要的临床和公共卫生意义，因为他们应该提供新的手段，黑色素瘤预防策略。本研究的目的是验证α-黑素细胞刺激激素（α-MSH）的中心假设，α-MSH是黑素生成所需的重要旁分泌因子，（即晒黑）对太阳辐射的反应，通过减少活性氧（ROS）的产生，增加抗氧化蛋白的表达和/或活性，并增强氧化性DNA损伤的修复。我们提出两个具体目标：1）检验α-MSH通过调节转录因子NF-E2相关因子（Nrf-2）的活性来发挥其抗氧化作用的假设，和2）检验p53的积累和转录活性对于α-MSH减少氧化性DNA损伤是必需的假设。该提议将定义a-MSH在hMC的UVR光保护中的新作用，其超越了其作为黑素生成诱导剂的经典已知作用，并且包括减少UV诱导的氧化DNA损伤，作为可能的主要保护机制。公共卫生相关性：皮肤恶性黑色素瘤（最致命的皮肤癌）的发病率继续上升。本研究的目的是证明α-黑素细胞刺激激素（α-MSH），皮肤晒黑反应的一个重要因素，保护黑素细胞免受紫外线的致癌作用，通过减少自由基造成的负担。在这项研究中，我们提出了调查的分子途径，通过它的α-MSH抵消紫外线诱导的氧化应激在人类黑素细胞，从而防止其恶性转化为黑色素瘤。