MITF from control of pigmentation to melanoma risk

摘要 人类皮肤的照相类型通常以1(红发)到6(深色构成色素)的渐变来描述 与紫外线敏感度和黑色素瘤风险相关，与此梯度平行的是色素痣的增加。 从较暗的照片类型到较亮的照片类型，在照片类型1(红发)处突然下降的渐变，在可见雀斑的位置 出乎意料地罕见，我们假设，并在小鼠模型中验证，BRAFveooE_E_诱导的色素沉着 红毛老鼠是“看不见的”，但实际上比基因上匹配的黑色老鼠要多得多 小鼠，由于缺乏暗色真黑素，临床上看不出来，但很容易通过荧光识别。 标记，并与显著升高的自发性黑色素瘤转化和UVA诱导相关 红发小鼠患黑色素瘤的风险，这种黑色素瘤的风险被追溯到红色色素，因为“白化-红发” 小鼠缺乏所有色素，并受到保护，不受自发的(先前发表的)、UVA诱导的或 过氧化氢诱导的黑色素瘤、自发的和UVA诱导的“看不见的”痣和黑色素瘤的发生 建议在NRASQ61的AIMS 1和2中研究 R色素模型，2“d最常见的人类雀斑和 黑色素瘤癌基因，以补充我们广泛的未发表的BRAFveooE数据，几个小分子 将测试可能降低黑色素诱导的黑色素瘤风险的方法，包括诱导黑暗 真黑素的合成，一个这样的例子已经被发现“揭示”在“看不见的”痣中的可见损害。 此外，被改造成等基因色素背景的荧光痣将被 从皮肤中进行流动分类，并对转录进行仔细检查，以机械地剖析途径和基因 (包括氧化还原)在皮肤白皙的个体中调节黑色素瘤风险的升高，只有少数 黑色素瘤是由先前存在的色素痣引起的，因此我们使用我们的模型来检查色素痣和总体黑色素瘤风险， 我们还发现，治疗帕金森病的L-多巴显著提高了麻黑素的合成 在红发患者中，除了是多巴胺前体外，L-多巴恰好是一种化学中间体。 黑色素生物合成、帕金森氏症和黑色素瘤长期以来一直相互关联，但 在缺乏机制解释的情况下，我们观察到小剂量L-多巴显著增加了黑色素瘤的风险 BRAFveooE是红发的，但在白化红小鼠模型中(不能产生红褐素或真黑素)，Aim 3将在NRAS061R红发模型上测试L-多巴的黑色素瘤因果关系，以及局部皮肤变暗是否可能 修改已经观察到的BRAFveooE的增强型黑色素瘤风险，最后，Aim 4将检验该假设 M ITF调节抗氧化途径的表达，该途径包括控制再生的酶 减少NADPH和谷胱甘肽-缓冲黑素细胞氧化应激的关键因素，其中一种酶， 线粒体酶NNT最近被证明调节黑素细胞氧化还原和黑素小体分化， 我们将测试NNT是M ITF转录靶点的证据，并从功能上仔细检查新发现的 NNT中的序列变异，被NCI合作者提名为人类家族性黑色素瘤候选基因。

Abstract Human skin phototypes are routinely described in a gradient of 1 (redhaired) to 6 (dark constitutive pigment) which correlates with UV sensitivity and risk of melanoma, Parallel to this gradient is the increase of nevi (moles) from darker to lighter phototypes, a gradient which abruptly drops at phototype 1 (redhaired) where visible nevi are unexpectedly rare, We hypothesized, and verified in murine models, that BRAFveooE_ induced nevi in redhaired mice are "invisible" but actually significantly more abundant compared to genetically matched black mice, They are clinically inapparent due to lack of dark eumelanin, but are easily identified via fluorescence tagging, and associated with profoundly elevated spontaneous melanoma transformation and UVA-induced melanoma risk in redhaired mice, This melanoma risk was traced to red pigment because "albino-redhaired" mice lack all pigment and are protected from either spontaneous (previously published), UVA-induced, or peroxide-induced melanoma, Spontaneous and UVA-induced "invisible" nevi and melanoma-genesis are proposed for study in Aims 1 and 2 for NRASQ61 R pigment models, the 2"d most common human nevus and melanoma oncogene, to complement our extensive unpublished data for BRAFveooE, Several small molecule approaches will be tested to potentially mitigate pheomelanin-induced melanoma risk including induction of dark eumelanin synthesis, One such example was already seen to "reveal" visible lesions in the "invisible" nevusbearing redhaired mice, In addition, the fluorescent nevi, engineered into isogenic pigment backgrounds, will be flow-sorted from skin and transcriptomically scrutinized to mechanistically dissect the pathways and genes (including redox) that mediate the elevated melanoma risk among fair skinned individuals, Only a minority of melanomas arise from pre-existing nevi, so we use our models to examine both nevi and overall melanoma risk, We also discovered that the Parkinson's Disease therapy L-Dopa significantly elevates pheomelanin synthesis in redheads, Separate from being a dopamine precursor, L-Dopa is coincidentally a chemical intermediate in melanin biosynthesis, Parkinson's Disease and melanoma have long been associated with one another, but lacking a mechanistic explanation, We observed that low dose L-Dopa significantly elevates melanoma risk in BRAFveooE redhaired, but not in albino-red mouse models (which cannot make pheomelanin or eumelanin), Aim 3 will test L-Dopa's melanoma causality in NRAS061R redhaired models and whether topical skin darkening may modify the enhanced melanoma risk already observed for BRAFveooE, Finally, Aim 4 will examine the hypothesis that M ITF regulates expression of an anti-oxidant pathway which includes enzymes controlling regeneration of reduced NADPH and glutathione-key factors buffering melanocyte oxidative stress, One such enzyme, the mitochondrial enzyme NNT, was recently shown to modulate melanocyte redox and melanosome differentiation, We will test evidence that NNT is a transcriptional target of M ITF and functionally scrutinize a newly identified sequence variant in NNT, nominated by NCI collaborators as a candidate familial melanoma gene in humans.