Recep. Protein Tyrosine Phosphatase-k Regulation of EGFR

描述(申请人提供)：拟议研究的长期目标是了解太阳紫外线(UV)照射损害人类皮肤并导致鳞状细胞皮肤癌的机制。来自太阳的紫外线辐射是对人类皮肤最常见和最有害的环境侮辱形式之一，皮肤是直接暴露在环境中的最大器官。世界各地的流行病学研究已经确立了鳞状细胞皮肤癌的发病率与暴露于太阳紫外线辐射之间的直接联系。皮肤癌是美国高加索人口中最常见的癌症类型，每年诊断的病例超过50万至100万例。据估计，美国每年的治疗费用在5亿至10亿美元之间。因此，皮肤癌是一个严重的公共卫生问题。了解太阳紫外线照射损伤皮肤并导致皮肤癌的分子机制将有助于更有效的预防和治疗。紫外线辐射对人类皮肤有害的主要机制有两个：1)改变DNA，导致基因突变，导致细胞转化；2)激活各种信号转导途径，最终上调损害皮肤的基因产物，促进有助于癌症形成的环境。越来越多的证据表明，表皮生长因子受体(EGFR)在皮肤肿瘤的发生中起着关键作用，是紫外线辐射刺激对皮肤有害的信号转导途径的主要驱动力。我们以前的研究已经证明，紫外线照射通过氧化抑制受体类型蛋白酪氨酸磷酸酶-kappa(RPTPK)来激活EGFR，RPTPK是EGFR的特异性负调控因子。这项建议的重点是研究RPTPK的调控和功能。拟议的研究将检验这样的假设，即RPTPK下调导致EGFR过度激活，从而促进鳞状细胞皮肤癌的形成。我们提出了四个具体的目标：1)研究RPTPK在紫外线诱导的转基因小鼠炎症和表皮增生中的作用；2)研究RPTPK的转录调控；3)在体内研究紫外线照射诱导的人皮肤中RPTPK的氧化作用；4)确定RPTPK在肿瘤细胞系和小鼠异种移植模型中的抑瘤作用。

DESCRIPTION (provided by applicant): The long term goal of the proposed research is to understand the mechanisms by which solar ultraviolet (UV) irradiation damages human skin and causes squamous cell skin cancer. UV irradiation from the sun is among the most common and harmful forms of environmental insult to human skin, the largest organ that is directly exposed to the environment. Epidemiological studies worldwide have established a direct connection between the incidence of squamous cell skin cancer and exposure to solar UV irradiation. Skin cancer is the most common type of cancer in the Caucasian population of the United States, with more than 500,000 to 1,000,000 cases diagnosed each year. The annual cost of treatment in the U.S. is estimated to be between $500 million and $1 billion. Therefore, skin cancer is a serious public health issue. Understanding molecular mechanisms by which solar UV irradiation damages skin and causes skin cancer will lead to more efficient prevention and treatment. UV irradiation is detrimental to human skin via two primary mechanisms: 1) altering DNA, which results in genetic mutations that can lead to cellular transformation, and 2) activation of a variety of signal transduction pathways, which ultimately up- regulate gene products that damage skin and promote an environment conductive to cancer formation. Accumulating evidence indicates that epidermal growth factor receptor (EGFR) plays pivotal roles in skin tumorigenesis and is a primary driving force by which UV irradiation stimulates signal transduction pathways that are harmful to the skin. Our previous studies have demonstrated that UV irradiation activates EGFR by oxidative inhibition of receptor-type protein tyrosine phosphatase-kappa (RPTPK), a specific negative regulator of EGFR. The focus of this proposal is to investigate regulation and function of RPTPK. The proposed studies will test the hypothesis that down-regulation of RPTPK leads to over-activation of EGFR, which promotes squamous cell skin cancer formation. Four Specific Aims are proposed: 1) examine the role of RPTPK in UV irradiation-induced inflammation and epidermal hyperplasia in transgenic mice, 2) investigate transcriptional regulation of RPTPK, 3) characterize UV irradiation-induced RPTPK oxidation in human skin in vivo, and 4) determine tumor suppressor property of RPTPK in cancer cell lines and mouse xenograft models.