Ultraviolet-Induced Signal Trasduction

描述（由申请人提供）：本申请中待检验的假设是，UVB诱导的c-Jun N-末端激酶（JNK）及其下游转录因子/核蛋白的激活在UVB诱导的细胞凋亡和皮肤癌发生中起功能性作用。因此，这些信号分子是开发化学预防剂以抑制UVB诱导的皮肤癌的潜在靶点。本申请的重点是鉴定和研究JNKs的新底物及其在细胞转化/致癌中的生物学功能。 解决这一假设的具体目标是： 具体目标1。为了确定JNK在UVB诱导的Statl和Stat 3磷酸化中的作用。具体目标2。探讨JNK在UVB诱导的组蛋白H3和H2 A磷酸化中的作用。 具体目标3。确定JNK、Stat 1、Stat 3和组蛋白H3和H2 A在UVB或TNF α诱导的细胞周期停滞、凋亡或细胞转化中的作用。具体目标4。确定JNK在UVB诱导的皮肤癌发生中的作用及其作为皮肤癌化学预防靶点的潜力。这些知识将导致更好地了解人类皮肤癌的发生，并促进设计更有效的药物用于人类皮肤癌的化学预防。

DESCRIPTION (provided by applicant): The hypothesis to be tested in this application is that UVB-induced activation of c-Jun N-terminal kinases (JNKs) and their downstream transcription factors/nuclear proteins plays a functional role in UVB-induced cellular apoptosis and skin carcinogenesis. Therefore these signaling molecules are potential targets for the development of chemopreventive agents to inhibit UVB-induced skin cancers. The focus of this application is to identify and study novel substrates of JNKs and their biological functions in cell transformation/carcinogenesis. The specific aims to address this hypothesis are: Specific Aim 1. To determine the role of JNKs in UVB-induced phosphorylation of Statl and Stat3. Specific Aim 2. To determine the role of JNKs in UVB-induced phosphorylation of histones H3 and H2A. Specific Aim 3. To determine the role of JNKs, Statl, Stat3 and histones H3 and H2A in UVB- or TNFalpha-induced cell cycle arrest, apoptosis or cell transformation. Specific Aim 4. To determine the role of JNKs in UVB-induced skin carcinogenesis and their potential as targets for chemoprevention of skin cancer. Such knowledge will lead to a better understanding of human skin carcinogenesis, and facilitate the design of more effective agents for chemoprevention of human skin cancer.