Liver regeneration is a complex process that involves a multitude of cellular functions, including primarily cell proliferation, apoptosis, inflammation, and metabolism. A number of signaling pathways that control these processes have been identified, and cross communication between them by direct protein-protein interactions has been shown to be crucial in orchestrating liver regeneration. Previously, we have identified a group of transcription factors capable of regulating liver cell growth and that may be involved in liver cancer development. The expression of some of their mouse counterpart genes was altered dramatically after liver injury and regeneration induced by CCl(4) in mice. In an effort to elucidate the molecular basis for liver regeneration through protein-protein interactions (PPI), a matrix mating Y2H approach was produced to generate a PPI network between a set of 32 regulatory proteins. Sixty-four interactions were identified, including 4 that had been identified previously. Ten of the interactions were further confirmed with GST pull-down and coimmunoprecipitation assays. Information provided by this PPI network may shed further light on the molecular mechanisms that regulate liver regeneration at the protein interaction level and ultimately identify regulatory factors that may serve as candidate drug targets for the treatment of liver diseases.

Activating transcription factor (ATF) 3 plays a role in determining cell fate and generates a variety of alternatively spliced isoforms in stress response. We have reported previously that splice variant ATF3deltaZip2, which lacks the leucine zipper region, is induced in response to various stress stimuli. However, its biological function has not been elucidated. By using cells treated with tumor necrosis factor-alpha and actinomycin D or cells overexpressing ATF3deltaZip2, we showed that ATF3deltaZip2 sensitizes cells to apoptotic cell death in response to tumor necrosis factor-alpha, at least in part through suppressing nuclear factor (NF)-kappaB-dependent transcription of anti-apoptotic genes such as cIAP2 and XIAP. ATF3deltaZip2 interacts with a p65 (RelA)-cofactor complex containing CBP/p300 and HDAC1 at NF-kappaB sites of the proximal promoter region of the cIAP2 gene in vivo and down-regulates the recruitment of CBP/p300. Our study revealed that ATF3deltaZip2 counteracts anti-apoptotic activity of NF-kappaB, at least in part, by displacing positive cofactor CBP/p300 and provides insight into the mechanism by which ATF3 regulates cell fate through alternative splicing in stress response.

Liver regeneration is a complex process that involves a multitude of cellular functions, including primarily cell proliferation, apoptosis, inflammation, and metabolism. A number of signaling pathways that control these processes have been identified, and cross communication between them by direct protein-protein interactions has been shown to be crucial in orchestrating liver regeneration. Previously, we have identified a group of transcription factors capable of regulating liver cell growth and that may be involved in liver cancer development. The expression of some of their mouse counterpart genes was altered dramatically after liver injury and regeneration induced by CCl(4) in mice. In an effort to elucidate the molecular basis for liver regeneration through protein-protein interactions (PPI), a matrix mating Y2H approach was produced to generate a PPI network between a set of 32 regulatory proteins. Sixty-four interactions were identified, including 4 that had been identified previously. Ten of the interactions were further confirmed with GST pull-down and coimmunoprecipitation assays. Information provided by this PPI network may shed further light on the molecular mechanisms that regulate liver regeneration at the protein interaction level and ultimately identify regulatory factors that may serve as candidate drug targets for the treatment of liver diseases.

ATF3 is a member of the mammalian activating transcription factor/cAMP responsive element binding protein (ATF/CREB) family of transcription factors. In this report, we demonstrate that, contrary to the implication of its name, ATF3 represses rather than activates transcription from promoters with ATF sites. We also present evidence suggesting that one possible mechanism by which ATF3 represses transcription is to stabilize inhibitory co-factors at the promoter. In addition, we describe a naturally occurring, alternatively spliced, form of ATF3: ATF3 delta Zip. ATF3 delta Zip lacks the leucine zipper domain and does not bind to DNA. In contrast to ATF3, ATF3 delta Zip stimulates transcription, presumably by sequestering inhibitory co-factors away from the promoter. It is possible that ATF3 delta Zip is a physiologically important regulator and that it, together with ATF3, regulates the expression of specific target genes.