CREB/ATF PROTEINS AND HEPATOCYTE GROWTH CONTROL

致癌病毒在定义参与细胞生长控制的细胞调节网络方面具有非常宝贵的价值。 B肝炎病毒X蛋白（pX）与肝癌发生有关，是一种双重转录激活因子; pX激活ras-raf-MAPK和JNK通路，通过直接相互作用，pX增加bZip转录因子（包括CREB、ATF 2和ATF 3）的转录效力。 CREB介导cAMP的转录反应，是促有丝分裂途径的下游效应子，调节c-fos表达，并且在发育中是必需的。 ATF 2在发育中也是必不可少的，并且是应激激活途径的下游效应物。 ATF 3在再生肝脏中表达，在应激反应中和EIA转化细胞中被诱导。 因此，我们的假设是，这些bZip蛋白介导的PX诱导的肝癌细胞的影响。 我们的长期目标是确定CREB/ATF/pX相互作用的结构和功能方面。 目的1通过描绘CREB（bZip）相互作用所需的最小功能pX区域来检查CREB（bZip）/pX相互作用的机制。 目的2和3研究CREB和ATF 2在PX介导的转化中的重要性以及CREB/ATF/PX相互作用在肝癌发生中的功能意义。 这些目标将采用条件，pX表达，永生化肝细胞系，其中pX表达与致癌转化。 我们的研究将定义：目标二：在转化过程中由pX激活的促有丝分裂途径和在pX诱导的转化过程中失调的细胞基因;目的3：CREB和ATF 2在pX介导的转化中的作用：a）通过构建CREB和ATF 2活性减弱的细胞系;和B）通过检查细胞转化过程中pX在细胞核中的作用。 这些研究将阐明CREB（bZip）/pX相互作用的机制，CREB/ATF蛋白在肝细胞生长控制中的作用，并提供与pX介导的肝癌发生相关的见解。 通过pX改变基因表达的机制的研究可能会产生重要的见解，在肝细胞中的致癌转化的一般过程。

Oncogenic viruses have been invaluable in defining cellular regulatory networks involved in cell growth control. The Hepatitis B virus X protein (pX), implicated in hepatocarcinogenesis, is a dual activator of transcription; pX activates the ras-raf-MAPK and JNK pathways, and by direct interaction, pX increases the transcriptional efficacy of bZip transcription factors, including CREB, ATF2 and ATF3. CREB mediates the transcriptional response of cAMP, is the downstream effector of mitogenic pathways, regulates c-fos expression, and is essential in development. ATF2 is also essential in development and the downstream effector of the stress-activated pathways. ATF3 is expressed in regenerating liver, is induced in response to stress and in EIA-transformed cells. Accordingly, our hypothesis is that these bZip proteins mediate cellular effects of pX-induced hepatocarcinogenesis. Our long-term goal is to define structural and functional aspects of CREB/ATF/pX interactions. Aim 1 examines the mechanism of CREB(bZip)/pX interactions by delineating a minimal, functional pX region required for CREB(bZip) interaction. Aims 2 and 3 examine the importance of CREB and ATF2 in pX-mediated transformation and the functional significance of CREB/ATF/pX interactions in hepatocarcinogenesis. These aims will be addressed employing conditional, pX-expressing, immortalized hepatocyte cell lines in which pX expression is linked to oncogenic transformation. Our studies will define: Aim 2: the mitogenic pathways activated by pX during transformation and cellular genes deregulated during pX-induced transformation; Aim 3: the role of CREB and ATF2 in pX-mediated transformation: a) by constructing cell lines in which the activity of CREB and ATF2 is attenuated; and b) by examining the role of pX in the nucleus during cellular transformation. These studies will elucidate the mechanism of CREB(bZip)/pX interactions, the role of CREB/ATF proteins in growth control in hepatocytes, and provide insights relevant to pX-mediated hepatocarcinogenesis. Studies on the mechanism of altered gene expression by pX are likely to yield important insights into the general process of oncogenic transformation in hepatocytes.