LIVER-REGENERATION .4. TRANSCRIPTIONAL CONTROL OF LIVER-REGENERATION

Determining what factors are responsible for initiating regeneration f ollowing partial hepatectomy or toxic damage, and how the Liver mainta ins differentiated functions while the hepatocytes are undergoing cell ular proliferation are central issues in understanding the molecular b ases of liver regeneration. Examination of-the transcriptional milieu in the regenerating liver provides clues to the answers to these quest ions, Growth factor-generated intracellular signals that trigger Liver regeneration result in activation via posttranslational modifications of latent, normally inactive transcription factors that preexist in t he liver. Two transcription factors that are activated by this mechani sm include posthepatectomy factor/nuclear factor-kappa B (PHF/NF-kappa B) and Stat3, Because cytokines such as tumor necrosis factor-alpha ( TNF-alpha), interleukin-1 (IL-1), and IL-6 can induce these factors in the liver, the finding of activated Stat3 and PHF/NF-kappa B suggests that these cytokines may play a role ill some aspects of growth regul ation during liver regeneration, Rapidly induced transcription factors , Stat3, PHF/NF-kappa B, and others are responsible for activation of the primary growth response or immediate-early genes, which play a rol e in regulating later phases of cell growth in regenerating liver and other mitogen-activated cells, Immediate-early genes encode many membe rs of diverse transcription factor families including the Jun-Fos-LRF- 1, nuclear receptor, and myc families to name a few, In this way a tra nscriptional cascade is established during the G1 phase of liver regen eration, Coexisting with these induced factors are liver-specific tran scription factors such as the CAAT enhancer binding proteins and hepat ocyte nuclear factors, which may interact with growth-induced factors to help the liver maintain metabolic homeostasis during regeneration. As a result the Liver is able to accomplish the goals of reestablishin g its mass while it maintains its functional capacity during regenerat ion.