The role of TC-PTP in skin carcinogenesis

描述（由申请人提供）：皮肤癌是美国最常见的癌症。它是由长期和过度暴露于紫外线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，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，从而导致皮肤癌的发生。一个重要的信号传导机制是酪氨酸磷酸化信号传导。磷酸化酪氨酸信号是由蛋白酪氨酸激酶（PTKs）和蛋白酪氨酸磷酸酶（PTPs）的抗活性调控的。PTKs已经被确定为致癌的关键因素，因此许多抗癌药物已经开发出针对这些蛋白质的药物。虽然目前的这些药物对某些癌症有效，但它们有副作用。因此，需要替代疗法来补充现有疗法。尚未对PTPs与皮肤癌的关系进行研究，因为之前的研究表明，在暴露于UVB辐射后，角质形成细胞中的PTPs会失活。然而，最近我们发现t细胞蛋白酪氨酸磷酸酶（TC-PTP）在中波紫外线或化学物质暴露后被激活。TC-PTP主要定位于角质形成细胞的细胞质中，在UVB照射下，它被转移到细胞核中，在那里它有助于信号换能器和转录激活子3 （Stat3）的失活，Stat3是一种众所周知的致癌蛋白。TC-PTP和类似的ptp可能是开发抗皮肤癌治疗的新靶点。我们的假设是TC-PTP在暴露于环境毒物后对Stat3信号转导的调控中起重要作用，TC-PTP的缺失会导致Stat3的组成性激活，进而促进皮肤癌的发生。本项目将采用分子和细胞方法实现以下目标：1)研究TC-PTP在角质细胞增殖、分化和存活中的功能，明确TC-PTP的核易位机制，确定其对角质细胞增殖的影响；2)通过两种皮肤特异性转基因小鼠模型，确定TC-PTP在环境性皮肤癌变中的潜在抑瘤作用。该研究将为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，从而有助于确定新的皮肤癌预防和治疗靶点。

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.