The role of TC-PTP in skin carcinogenesis

TC-PTP在皮肤癌发生中的作用

• 批准号: 8721412
• 负责人: Dae Joon Kim
• 金额: $ 33.3万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721412
• 关键词: Adverse effects; Alternative Therapies; Antineoplastic Agents; Apoptosis; Applications Grants; Basal Cell; Cell Line; Cell Nucleus; Cell Proliferation; Cells; Chemical Exposure; Chemicals; Chronic; Cytokine Signaling; Cytoplasm; DNA Damage; Development; Disease; Environmental Carcinogens; Environmental Exposure; Environmental Risk Factor; Epidermis; Epithelial; Exposure to; Family; Goals; Growth; Hematopoiesis; Housekeeping Gene; Immune response; Intervention; Laboratories; Lead; Link; Malignant Neoplasms; Mediating; Mediator of activation protein; Molecular; Mus; Mutation; National Cancer Institute; Nuclear Translocation; Oncogenic; Pharmacologic Substance; Phosphorylation; Phosphotyrosine; Play; Predisposition; Prevention; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Proteins; Proto-Oncogenes; Regulation; Reporting; Research; Role; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Carcinogenesis; Skin Neoplasms; Stat3 protein; Study Section; Sunlight; System; T-cell protein tyrosine phosphatase; Toxic Environmental Substances; Transgenic Mice; Tumor Promotion; Tyrosine; Tyrosine Phosphorylation; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; United States; assault; cancer diagnosis; cancer therapy; carcinogenesis; chemical carcinogen; dimethylbenzanthracene; effective therapy; high risk; human disease; inhibitor/antagonist; insight; irradiation; keratinocyte; keratinocyte differentiation; member; mouse model; new therapeutic target; novel; overexpression; programs; public health relevance; skin cancer prevention; therapeutic target; toxicant; tumor; ultraviolet irradiation

DESCRIPTION (provided by applicant): Skin cancer is the most common form of cancer in the United States. It is caused by chronic and excessive exposure to environmental factors like ultraviolet (UV) radiation and chemical toxicants. UV radiation and chemical toxicants contribute to the development of skin cancer by creating DNA damage that can yield mutations in housekeeping genes and proto-oncogenes which disrupt intracellular signaling mechanisms. One vital signaling mechanism is tyrosine phosphorylation signaling. Phosphotyrosine signaling is regulated by the counter-activities of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). PTKs have been established as critical contributors in carcinogenesis, thus many anti-cancer drugs have been developed that target these proteins. Although these current pharmaceuticals have been effective in some cancers, they have side effects. Therefore, alternative therapies are needed to supplement the current ones. PTPs have not been studied in regards to skin cancer because it had previously been shown that PTPs are inactivated in keratinocytes upon exposure to UVB radiation. However, recently we have discovered that T-cell protein tyrosine phosphatase (TC-PTP) is activated following UVB or chemical exposure. TC-PTP is mainly localized to the cytoplasm in keratinocytes and upon UVB irradiation it is translocated to the nucleus where it contributes to the inactivation of signal transducer and activator of transcription 3 (Stat3), a well-known oncogenic protein. TC-PTP, and similar PTPs, may be novel targets for the development of anti-skin cancer therapies. Our hypothesis is that TC-PTP plays an important role in the regulation of Stat3 signal transduction following exposure to environmental toxicants, and loss of TC-PTP will lead to constitutive activation of Stat3, which in turn promotes the development of skin cancer. The proposed project will use molecular and cellular approaches to accomplish the following objectives: 1) examine the function of TC-PTP in keratinocyte proliferation, differentiation, and survival, and define the mechanism of nuclear translocation of TC-PTP to determine its impact on keratinocyte proliferation; and 2) determine the potential tumor suppressive role(s) of TC-PTP in environmental skin carcinogenesis by using two skin-specific transgenic mouse models. This research will provide new insights into the specific functional roles of PTP in the cellular mechanisms involved in environmental skin carcinogenesis, which in turn will help identify novel therapeutic targets for skin cancer prevention and treatment.

描述（由申请人提供）：皮肤癌是美国最常见的癌症形式。它是由长期过度暴露于紫外线 (UV) 辐射和化学毒物等环境因素引起的。紫外线辐射和化学毒物会造成 DNA 损伤，从而导致管家基因和原癌基因发生突变，从而破坏细胞内信号传导机制，从而促进皮肤癌的发生。一种重要的信号传导机制是酪氨酸磷酸化信号传导。磷酸酪氨酸信号传导受蛋白酪氨酸激酶 (PTK) 和蛋白酪氨酸磷酸酶 (PTP) 的反作用调节。 PTK 已被确定为致癌的关键因素，因此已开发出许多针对这些蛋白质的抗癌药物。尽管目前的这些药物对某些癌症有效，但它们也有副作用。因此，需要替代疗法来补充当前的疗法。尚未对 PTP 与皮肤癌的关系进行研究，因为之前已表明，暴露于 UVB 辐射后，角质形成细胞中的 PTP 会失活。然而，最近我们发现 T 细胞蛋白酪氨酸磷酸酶 (TC-PTP) 在 UVB 或化学品暴露后被激活。 TC-PTP 主要定位于角质形成细胞的细胞质，在 UVB 照射后，它会转移到细胞核，从而导致信号转导子和转录激活子 3 (Stat3)（一种众所周知的致癌蛋白）失活。 TC-PTP 和类似的 PTP 可能是开发抗皮肤癌疗法的新靶点。我们的假设是，TC-PTP在环境毒物暴露后对Stat3信号转导的调节中发挥重要作用，TC-PTP的丧失将导致Stat3的组成性激活，进而促进皮肤癌的发生。该项目将利用分子和细胞方法实现以下目标：1）研究TC-PTP在角质形成细胞增殖、分化和存活中的功能，并明确TC-PTP核转位的机制，以确定其对角质形成细胞增殖的影响； 2) 通过使用两种皮肤特异性转基因小鼠模型确定 TC-PTP 在环境皮肤癌发生中的潜在肿瘤抑制作用。这项研究将为 PTP 在环境皮肤癌发生的细胞机制中的具体功能作用提供新的见解，从而有助于确定皮肤癌预防和治疗的新治疗靶点。