CREB/ATF PROTEINS AND HEPATOCYTE GROWTH CONTROL

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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.