Chromatin Remodeling in UVR Induced Melanogenesis

描述(由申请人提供) 皮肤黑素细胞通过合成黑色素并将其分布到周围细胞，为抵御紫外线(UV)辐射对DNA的损伤提供了主要的生理防御。暴露在紫外线辐射下与正常黑素细胞转化为黑色素瘤高度相关。调节对紫外线辐射的反应的机制和导致致癌状态的步骤尚未阐明。暴露在紫外线辐射下的一个标志是通过增强黑色素合成所需基因的转录而增加色素沉着。细胞还通过激活导致细胞周期停滞、DNA修复和细胞凋亡的通路来对紫外线辐射做出反应。为了了解黑素细胞如何对紫外线辐射做出反应，有必要对其中涉及的分子机制进行表征。基因表达的激活通常涉及染色质结构的改变，以使其更容易被转录机制所利用。SWI/SNF酶是一种多亚基复合体，它利用三磷酸腺苷的水解来重塑染色质结构，促进转录因子的结合。它们作为肿瘤抑制因子，参与基因调控和细胞周期控制。 初步证据表明，SWI/SNF酶是激活黑素细胞特异性基因(酪氨酸酶、trp1和trp2)以及调节细胞周期停滞(P21)和细胞凋亡(Bcl2)所必需的。这项建议旨在调查SWI/SNF酶在紫外线辐射反应中所起的作用。具体目标1将确定SWI/SNF酶是否需要增强酪氨酸酶、trp1和trp2的表达，以及在紫外线照射下对其他基因的调节。具体目标2将通过观察染色质结构和转录因子结合的变化，确定紫外线辐射导致黑素细胞特异性基因酪氨酸酶激活的机制。具体目标3将确定SWI/SNF酶在细胞周期控制中的作用。

DESCRIPTION (provided by applicant) Cutaneous melanocytes provide the major physiologic defense against the DNA damaging effects of ultraviolet (UV) radiation by synthesizing and distributing melanin to surrounding cells. Exposure to UV radiation is highly correlated with the transformation of normal melanocytes into melanoma. The mechanisms regulating the response to UV radiation and the steps leading to the oncogenic state have not been elucidated. A hallmark of exposure to UV radiation is an increase in pigmentation by enhanced transcription of genes required for melanin synthesis. Cells also respond to UV radiation by activation of pathways leading to cell cycle arrest, DNA repair, and apoptosis. To understand how a melanocyte responds to UV radiation, it is necessary to characterize the molecular mechanism involved. Activation of gene expression often involves alterations in chromatin structure to make it more accessible to the transcriptional machinery. SWI/SNF enzymes are multisubunit complexes that utilize the hydrolysis of ATP to remodel chromatin structure and facilitate transcription factor binding. They act as tumor suppressors, and are involved in gene regulation and cell cycle control. Preliminary evidence suggests that SWI/SNF enzymes are required for the activation of melanocyte specific genes (tyrosinase, trp1, and trp2) and for genes regulating cell cycle arrest (p21) and apoptosis (Bcl2). This proposal seeks to investigate the role that SWI/SNF enzymes play in the response to UV radiation. Specific Aim 1 will determine whether SWI/SNF enzymes are required for the enhanced expression of tyrosinase, trp1, and trp2 and for the modulation of other genes upon exposure to UV radiation. Specific Aim 2 will identify the mechanisms by which UV radiation results in activation of a melanocyte specific gene tyrosinase, by looking at changes in chromatin structure and transcription factor binding. Specific Aim 3 will determine a role for SWI/SNF enzymes in cell cycle control.