TYROSINASE RELATED PROTEIN-1 AND BROWN OCA

酪氨酸酶相关蛋白-1 和棕色 OCA

• 批准号: 2732867
• 负责人: RAYMOND E BOISSY
• 金额: $ 23.38万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-10 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2732867
• 关键词: biosynthesis; clinical research; enzyme mechanism; gene mutation; human subject; intermolecular interaction; melanins; melanocyte; molecular pathology; monophenol monooxygenase; pigmentation; pigmentation disorders; skin; tissue /cell culture; transfection; tyrosine

DESCRIPTION: (Adapted from the applicant's abstract) - TRP-1, a member of the family of melanocyte-specific gene products involved in melanin synthesis, is a scientific enigma. Of the group of molecules, TRP-1 was identified serendipitously by several independent groups attempting to clone tyrosinase, the c-locus protein. This unveiling of TRP-1 resulted because antisera generated against tyrosinase had, unbeknownst at the time, cross-reacted with TRP-1. This illustrates another interesting feature of TRP-1, an intracellular protein: it appears to be extremely immunogenic. Serum antibodies and autoreactive T-cells against TRP-1 have been identified in patients with melanoma. Also, the appearance of TRP-1 antibodies correlates with the expression of vitiligo in an avian model, the Smyth chicken. Of interest are reports of autoantibodies recognizing a glycoprotein of 75 kDA (the m.w. of TRP-1) in patients with vitiligo which may be TRP-1. However, despite the prominence of TRP-1 in scientific/medical research, the role of TRP-1 in melanogenesis has been elusive. The applicants are certain that mutations of TRP-1 result in the synthesis of brown as opposed to black pelage in mice. However, the role of TRP-1 in human hair, as well as skin, pigmentation or how mutations in TRP-1 affect these tissues, has not been elucidated. The applicants propose to analyze the molecular role of TRP-1 in the synthesis of melanin using three avenues of investigation. First they will investigate how TRP-1 regulates the catalytic function of tyrosinase/TRP-1 and/or TRP-2, physically interacts with tyrosinase/TRP-2, and expresses a putative catalytic function(s) using defined melanoma cells and fibroblasts transfected with TRP-1 cDNA and the Matchmaker Two-Hybrid System for analyzing protein interactions. Second, mutational mapping of molecular domains responsible for these functions of TRP-1 will be addressed. Third, melanocytes from patients with tyrosinase-positive OCA expressing mutations affecting TRP-1, and from mice carrying mutant alleles at the brown locus, will be analyzed for defects in melanin synthesis. These studies will elucidate the function of TRP-1, its interaction with other melanocyte-specific gene products, and its role in the pathophysiology of human pigmentary diseases, specifically Brown OCA. These studies will also contribute to our knowledge of melanogenesis and the role of the melanocyte in the skin.

描述：（改编自申请人的摘要）- TRP-1，成员 黑色素细胞特异性基因产物家族 合成，是一个科学之谜。 在这组分子中，TRP-1是 几个试图克隆的独立小组偶然发现了它 酪氨酸酶，C基因座蛋白。 TRP-1的推出是因为 产生的抗酪氨酸酶的抗血清，当时并不知道， 与TRP-1交叉反应。 这说明了另一个有趣的特点， TRP-1，一种细胞内蛋白：它似乎具有极强的免疫原性。 已经鉴定了针对TRP-1的血清抗体和自身反应性T细胞 在黑色素瘤患者中。 TRP-1抗体的出现 与鸟类模型中白癜风的表达相关， 鸡 令人感兴趣的是关于自身抗体识别 75 kDA的糖蛋白（m.w. TRP-1）在白癜风患者中， 可能是TRP-1。 然而，尽管TRP-1在 在科学/医学研究中，TRP-1在黑素生成中的作用已经被证实。 难以捉摸。 申请人确信TRP-1的突变导致了TRP-1基因的突变。 在老鼠身上合成棕色而不是黑色的皮毛。 但是，作用 TRP-1在人类的头发，以及皮肤，色素沉着或如何突变的TRP-1 影响这些组织，尚未阐明。 本申请人提出分析TRP-1在细胞凋亡中的分子作用。 黑色素的合成使用三种途径的调查。 首先他们会 研究TRP-1如何调节酪氨酸酶/TRP-1的催化功能 和/或TRP-2，与酪氨酸酶/TRP-2物理相互作用，并表达酪氨酸酶/TRP-2， 使用确定的黑素瘤细胞和成纤维细胞的推定催化功能 转染TRP-1 cDNA和Matchmaker双杂交系统， 分析蛋白质相互作用。 第二，分子突变定位， 负责TRP-1的这些功能的域将被处理。 第三、 酪氨酸酶阳性OCA表达突变患者的黑素细胞 影响TRP-1，并且来自在棕色位点携带突变等位基因的小鼠， 将分析黑色素合成缺陷。 这些研究将 阐明TRP-1的功能及其与其他 黑素细胞特异性基因产物，及其在黑素细胞增生症病理生理学中的作用 人类色素性疾病，特别是棕色OCA。 这些研究还将 有助于我们了解黑素生成和黑素细胞 在皮肤上。

项目成果

Altered protein localization in melanocytes from Hermansky-Pudlak syndrome: support for the role of the HPS gene product in intracellular trafficking.

Hermansky-Pudlak 综合征黑素细胞中蛋白质定位的改变：支持 HPS 基因产物在细胞内运输中的作用。

• 发表时间: 1998
• 期刊: Laboratory investigation; a journal of technical methods and pathology
• 作者: Boissy,RE;Zhao,Y;Gahl,WA
• 通讯作者: Gahl,WA

Molecular and functional characterization of sodium--hydrogen exchanger in skin as well as cultured keratinocytes and melanocytes.

皮肤以及培养的角质形成细胞和黑素细胞中钠-氢交换器的分子和功能表征。

• DOI: 10.1016/s0005-2736(01)00273-5
• 发表时间: 2001
• 期刊: Biochimica et biophysica acta
• 作者: Sarangarajan,R;Shumaker,H;Soleimani,M;LePoole,C;Boissy,RE
• 通讯作者: Boissy,RE

Microphthalmia-associated transcription factor (MITF) locus lacks linkage to human vitiligo or osteopetrosis: an evaluation.

小眼相关转录因子（MITF）基因座与人类白癜风或骨石症缺乏联系：一项评估。

• DOI: 10.1111/j.1600-0749.1999.tb00512.x
• 发表时间: 1999
• 期刊: Pigment cell research
• 作者: Tripathi,RK;Flanders,DJ;Young,TL;Oetting,WS;Ramaiah,A;King,RA;Boissy,RE;Nordlund,JJ
• 通讯作者: Nordlund,JJ

Altered gene expression in melanocytes exposed to 4-tertiary butyl phenol (4-TBP): upregulation of the A2b adenosine receptor 1.

暴露于 4-叔丁基苯酚 (4-TBP) 的黑素细胞中基因表达发生改变：A2b 腺苷受体 1 上调。

• DOI: 10.1046/j.1523-1747.1999.00756.x
• 发表时间: 1999
• 期刊: The Journal of investigative dermatology.
• 作者: LePoole,IC;Yang,F;Brown,TL;Cornelius,J;Babcock,GF;Das,PK;Boissy,RE
• 通讯作者: Boissy,RE