The role of TC-PTP in skin carcinogenesis

描述(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在紫外线(UV)辐射和化学毒物等环境因素中引起的。紫外线辐射和化学毒物会造成DNA损伤，导致看家基因和原癌基因突变，从而扰乱细胞内信号机制，从而导致皮肤癌的发生。一个重要的信号机制是酪氨酸磷酸化信号。蛋白酪氨酸激酶(PTKs)和蛋白酪氨酸磷酸酶(PTPs)的反向活性调节了磷酸化酪氨酸信号转导。PTKs已被证实是癌症发生的关键因素，因此许多针对这些蛋白的抗癌药物已被开发出来。尽管这些目前的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现有的疗法。PTPs与皮肤癌的关系尚未被研究过，因为此前已有研究表明，PTPs在暴露于UVB辐射后在角质形成细胞中失活。然而，我们最近发现，T细胞蛋白酪氨酸磷酸酶(TC-PTP)在紫外线或化学暴露后被激活。TC-PTP主要定位于角质形成细胞的胞浆，经UVB照射后移位到胞核，导致信号转导和转录激活因子3(STAT3)失活，STAT3是已知的致癌蛋白。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在环境毒物暴露后对STAT3信号转导的调节中起重要作用，TC-PTP的缺失将导致STAT3的结构性激活，进而促进皮肤癌的发生发展。该项目将使用分子和细胞方法来完成以下目标：1)检测TC-PTP在角质形成细胞增殖、分化和存活中的功能，并确定TC-PTP的核转位机制，以确定其对角质形成细胞增殖的影响；以及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(S)。这项研究将对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.