Regulation of melanogenesis via FBXO11-mediated tyrosinase degradation

通过 FBXO11 介导的酪氨酸酶降解调节黑素生成

• 批准号: 9088354
• 负责人: PRASHIELA MANGA
• 金额: $ 8.48万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9088354
• 关键词: Albinism; Biology; Cell Cycle; Cell Cycle Proteins; Cell Cycle Regulation; Cell Survival; Cells; Chemicals; Complex; Cullin Proteins; Cutaneous; Data; Development; Disease; Down-Regulation; Endoplasmic Reticulum; Ensure; Enzymes; Etiology; Exhibits; Exposure to; Eye; F Box Domain; F-Box Proteins; Fatty Acids; Funding Mechanisms; Genes; Genetic Polymorphism; Genetic Transcription; Golgi Apparatus; Grant; Hair; Health; Hydrophthalmos; Hypopigmentation; Link; Linoleic Acids; Macular degeneration; Malignant Neoplasms; Mediating; Melanins; Melanogenesis; Melanosomes; Membrane Proteins; Monophenol Monooxygenase; Oculocutaneous Albinism; Okadaic Acid; Optic tract structure; Organelles; Parkinson Disease; Pathogenesis; Phenols; Phosphorylation; Pigmentation Disorders; Pigmentation physiologic function; Pigments; Play; Process; Production; Proteins; Radiation induced damage; Reaction; Regulation; Risk; Role; Skin; Skin Cancer; Skin Pigmentation; Skin tanning; Stimulus; Stress; System; TP53 gene; Translations; UV Radiation Exposure; Ubiquitin; Ultraviolet Rays; Up-Regulation; Vitiligo; effective therapy; enzyme activity; mRNA Expression; melanocyte; melanoma; multicatalytic endopeptidase complex; overexpression; prevent; protein degradation; protein transport; response; trafficking; ubiquitin ligase; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Tyrosinase catalyzes the first and rate-limiting reaction during the synthesis of melanin, the pigment that protects skin against ultraviolet radiation-induced damage, thus reducing the risk of developing cutaneous cancers. Disruption of tyrosinase folding and trafficking results in several forms of oculocutaneous albinism. In addition, tyrosinase polymorphisms are associated with increased risk of developing vitiligo and melanoma, and the protein may also play a role in Parkinson's disease, macular degeneration, and congenital glaucoma. Tyrosinase is also a determinant of skin pigmentation. Enzyme activity varies as much as ten-fold in lightly versus darkly pigmented skin; however, mRNA expression levels are remarkably similar. Tyrosinase regulation is therefore post-translational. Our objective is to elucidate the mechanisms that regulate melanin synthesis and characterize the pathogenesis of tyrosinase-related disorders. In this study, we aim to define the role of the Skp, Cullin, F-box (SCF) containing complexes, particularly the FBXO11 component, in tyrosinase regulation. SCF is a multi-protein E3 ubiquitin ligase complex that is a crucial component of the ubiquitin proteasome system (UPS). SCF complexes catalyze the ubiquitylation of proteins, thereby targeting them for proteasomal degradation. The F Box family protein FBXO11 has recently been implicated in the degradation of tyrosinase, while downregulation of FBXO11 is associated with the depigmentation disorder vitiligo. Previous studies as well as our own have demonstrated that melanocytes with reduced FBXO11 expression display increased levels of tyrosinase. Conversely, melanocytes overexpressing FBXO11 exhibit decreased levels of tyrosinase. In Specific Aim 1, we will investigate the mechanisms involved in FBXO11-mediated tyrosinase targeting. A number of external stimuli, such as exposure to vitiligo-inducing phenols or fatty acids, promote a reduction in tyrosinase levels. In Specific Aim 2.1, we will explore whether these stimuli promote FBXO11-mediated degradation of tyrosinase. In addition, p53, which promotes tyrosinase expression in response to ultraviolet light exposure, is itself a target of FBXO11. In Specific Aim 2.2, we will determine whether p53 is also targeted by FBXO11 in the melanocyte and whether degradation impacts tyrosinase levels. Given the critical role of p53 in cell cycle regulation and cell survival, FBXO1 may also play a role in determining melanocyte viability. We will thus also explore the effects of FXBO11 expression on melanocyte viability following exposure to stress induced by ultraviolet light or vitiligo-inducing phenols in Specific Aim 2.3. FBXO11 may thus play a key role in the regulation of normal pigmentation and in the pathogenesis of pigmentation disorders such as vitiligo. Understanding the role of this protein in the melanocyte will be crucial for delineating he etiology of pigmentation disorders and developing effective therapies.

描述（由申请人提供）：酪氨酸酶催化黑色素合成过程中的第一个限速反应，黑色素是一种保护皮肤免受紫外线辐射引起的损伤的色素，从而降低患皮肤癌的风险。酪氨酸酶折叠和运输的中断导致几种形式的眼皮肤白化病。此外，酪氨酸酶多态性与白癜风和黑色素瘤的风险增加有关，该蛋白质也可能在帕金森病，黄斑变性和先天性青光眼中发挥作用。 酪氨酸酶也是皮肤色素沉着的决定因素。浅色皮肤与深色皮肤的酶活性差异高达十倍;然而，mRNA表达水平非常相似。因此酪氨酸酶调节是翻译后的。我们的目标是阐明调节黑色素合成的机制，并描述酪氨酸酶相关疾病的发病机制。在这项研究中，我们的目的是确定的Skp，Cullin，F-盒（SCF）含有复合物，特别是FBXO 11组件，在酪氨酸酶调节的作用。SCF是一种多蛋白E3泛素连接酶复合物，是泛素蛋白酶体系统（UPS）的重要组成部分。SCF复合物催化蛋白质的泛素化，从而靶向它们进行蛋白酶体降解。最近发现F Box家族蛋白FBXO 11参与酪氨酸酶的降解，而FBXO 11的下调与色素脱失性白癜风有关。先前的研究以及我们自己的研究已经证明，FBXO 11表达减少的黑素细胞显示酪氨酸酶水平增加。相反，过表达FBXO 11的黑素细胞表现出酪氨酸酶水平降低。在具体目标1中，我们将研究FBXO 11介导的酪氨酸酶靶向机制。 许多外部刺激，如暴露于白癜风诱导酚或脂肪酸，促进酪氨酸酶水平的降低。在具体目标2.1中，我们将探讨这些刺激是否促进FBXO 11介导的酪氨酸酶降解。此外，p53，促进酪氨酸酶的表达，响应紫外线曝光，本身是FBXO 11的目标。在第2.2节中，我们将确定 p53是否也被黑素细胞中的FBXO 11靶向，以及降解是否影响酪氨酸酶水平。鉴于p53在细胞周期调节和细胞存活中的关键作用，FBXO 1也可能在决定黑素细胞活力中发挥作用。因此，我们还将探讨FXBO 11表达对黑素细胞活力的影响，暴露于紫外线或白癜风诱导酚类诱导的应激后，在特定目标2.3中。因此，FBXO 11可能在正常色素沉着的调节和色素沉着疾病（如白癜风）的发病机制中发挥关键作用。了解这种蛋白在黑素细胞中的作用对于阐明色素沉着疾病的病因和开发有效的治疗方法至关重要。