Recep. Protein Tyrosine Phosphatase-k Regulation of EGFR

接收。

• 批准号: 8281452
• 负责人: GARY J FISHER
• 金额: $ 34.99万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8281452
• 关键词: Acute; Antioxidants; Apoptosis; Biological Process; Cancer Biology; Cancer cell line; Caucasians; Caucasoid Race; Cell Proliferation; Cell Surface Receptors; Cell Survival; Cell physiology; Chemoprevention; Chronic; Communication; Contact Inhibition; Cutaneous; DNA; DNA Damage; Data; Diagnosis; Docking; Down-Regulation; Environment; Environmental Risk Factor; Enzymes; Epidemiologic Studies; Epidermal Growth Factor Receptor; Epithelial; Equilibrium; Exposure to; Family; Foundations; Gene Expression; Gene Mutation; Goals; Growth; Human; Hyperplasia; In Vitro; Incidence; Inflammation; Lead; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Metabolism; Modeling; Molecular; Mus; Normal Cell; Notch Signaling Pathway; Organ; Pathology; Pathway interactions; Phosphorylation; Physiology; Play; Population; Prevention; Prognostic Marker; Property; Protein Dephosphorylation; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Proteins; Public Health; Receptor Activation; Receptor Down-Regulation; Receptor Inhibition; Regulation; Research; Role; Signal Transduction Pathway; Site; Skin; Skin Aging; Skin Cancer; Solid Neoplasm; Squamous Cell; Stream; Structure; Substrate Specificity; Sun Exposure; Testing; The Sun; Transcriptional Regulation; Transforming Growth Factor beta; Transgenic Mice; Transgenic Organisms; Treatment Cost; Tumor Suppressor Proteins; Tyrosine; Tyrosine Phosphorylation; United States; Up-Regulation; Xenograft Model; Xenograft procedure; cancer type; driving force; improved; in vivo; metaplastic cell transformation; migration; mouse model; notch protein; novel; oxidation; premature; protective effect; receptor; receptor function; response; tumor; tumorigenesis; ultraviolet irradiation

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.

描述（由申请人提供）：拟议研究的长期目标是了解太阳紫外线（UV）照射损害人体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体皮肤最常见和最有害的环境损害形式之一，皮肤是直接暴露于环境的最大器官。世界范围内的流行病学研究已确定鳞状细胞皮肤癌的发病率与太阳紫外线照射之间存在直接联系。皮肤癌是美国白种人中最常见的癌症类型，每年诊断出超过 500,000 至 1,000,000 例病例。美国每年的治疗费用估计在 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害皮肤并导致皮肤癌的分子机制将有助于更有效地预防和治疗。紫外线照射通过两种主要机制对人体皮肤有害：1) 改变 DNA，导致基因突变，从而导致细胞转化；2) 激活多种信号转导途径，最终上调损伤皮肤的基因产物并促进有利于癌症形成的环境。越来越多的证据表明，表皮生长因子受体（EGFR）在皮肤肿瘤发生中发挥着关键作用，并且是紫外线照射刺激对皮肤有害的信号转导途径的主要驱动力。我们之前的研究表明，紫外线照射通过氧化抑制受体型蛋白酪氨酸磷酸酶-κ（RPTPK）（EGFR的特异性负调节因子）来激活EGFR。该提案的重点是研究 RPTPK 的监管和功能。拟议的研究将检验 RPTPK 下调导致 EGFR 过度激活的假设，从而促进鳞状细胞皮肤癌的形成。提出了四个具体目标：1）检查 RPTPK 在转基因小鼠中紫外线照射诱导的炎症和表皮增生中的作用，2）研究 RPTPK 的转录调控，3）表征体内人皮肤中紫外线照射诱导的 RPTPK 氧化，4）确定 RPTPK 在癌细胞系和小鼠异种移植模型中的肿瘤抑制特性。