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形式。它是由长期和过度暴露于环境因素，如紫外线（UV）辐射和化学毒物引起的。紫外线辐射和化学毒物通过造成DNA损伤而导致管家基因和原癌基因突变，从而破坏细胞内信号传导机制，从而促进皮肤癌的发展。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（PTPs）的反活性调节。PTK已被确定为致癌的关键贡献者，因此已经开发了许多靶向这些蛋白质的抗癌药物。虽然目前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目前的疗法。尚未研究PTP与皮肤癌的关系，因为先前已显示PTP在暴露于UVB辐射时在角质形成细胞中失活。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照射后，它会转移到细胞核，在那里它有助于信号转导和转录激活因子3（Stat 3）（一种众所周知的致癌蛋白）的失活。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Stat 3信号转导的调节中起着重要作用，TC-PTP的缺失将导致Stat 3的组成性激活，这反过来又促进皮肤癌的发生。本研究拟采用分子和细胞学方法，实现以下目标：1）研究TC-PTP在角质形成细胞增殖、分化和存活中的作用，明确TC-PTP的核转位机制，探讨其对角质形成细胞增殖的影响;（2）通过两种皮肤特异性转基因小鼠模型，确定TC-PTP在环境皮肤癌变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特定功能作用提供新的见解，这反过来将有助于确定皮肤癌预防和治疗的新治疗靶点。

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.