Regulation of melanogenesis via FBXO11-mediated tyrosinase degradation

描述（由申请人提供）：酪氨酸酶在黑色素合成过程中催化第一反应和限速反应，黑色素保护皮肤免受紫外线辐射引起的损伤，从而降低患皮肤癌的风险。酪氨酸酶折叠和运输的破坏导致几种形式的皮肤白化病。此外，酪氨酸酶多态性与白癜风和黑色素瘤的发病风险增加有关，酪氨酸酶也可能在帕金森病、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。在浅色皮肤和深色皮肤中，酶的活性相差高达10倍；然而，mRNA表达水平非常相似。因此酪氨酸酶的调节是翻译后的。我们的目的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，我们的目标是确定Skp， Cullin, F-box （SCF）复合物，特别是FBXO11成分，在酪氨酸酶调节中的作用。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。fbox家族蛋白FBXO11最近被认为与酪氨酸酶的降解有关，而FBXO11的下调与脱色障碍白癜风有关。先前的研究和我们自己的研究都表明，FBXO11表达减少的黑素细胞显示酪氨酸酶水平增加。相反，过表达FBXO11的黑素细胞表现出酪氨酸酶水平下降。在Specific Aim 1中，我们将研究fbxo11介导的酪氨酸酶靶向的机制。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Specific Aim 2.1中，我们将探讨这些刺激是否促进fbxo11介导的酪氨酸酶降解。此外，在紫外线照射下促进酪氨酸酶表达的p53本身就是FBXO11的靶标。在具体目标2.2中，我们将确定

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.