RAPID ACTIVATION OF LATENT TRANSCRIPTION FACTOR COMPLEXES REFLECTS INITIATING SIGNALS IN LIVER-REGENERATION

Liver regeneration following partial hepatectomy represents a physiolo gic response to a growth stimulus occurring in the intact animal. Unde rstanding what growth factors and cytokines trigger liver regeneration will provide insights into recovery from hepatic injury mediated by v iruses and toxins, and promote an understanding of normal cellular gro wth control. The modification of pre-existing latent transcription fac tors in the remnant liver by extracellular signals immediately post-he patectomy provides a mechanism for the transcriptional activation of p rimary or immediate early growth response genes, thereby establishing a transcriptional cascade. Two factors activated within minutes to hou rs post-hepatectomy in a protein synthesis-independent fashion include PHF/NF-kappa B and Stat3. Interestingly, these factors are commonly a ctivated by cytokines such as TNF alpha, IL-1 and IL-6 suggesting that there may be a connection between cytokine release and the onset of l iver regeneration. In addition to these known transcription factor com plexes, we have used a reporter gene assay in transgenic mice to attem pt to identify promoter sequences that are responsible for the transcr iptional activation of the liver-restricted IGFBP-1 immediate early ge ne within minutes posthepatectomy Studies so far indicate that an upst ream region of 800 bp is able to confer both tissue-restricted express ion and induction during liver regeneration. Identification of the tra nscriptional activators or liver regeneration factors responsible for this induction will result in further dissection of the initiating sig nals.