LAP (NF-IL-6), A TISSUE-SPECIFIC TRANSCRIPTIONAL ACTIVATOR, IS AN INHIBITOR OF HEPATOMA-CELL PROLIFERATION

During postnatal liver development, LAP (NF-IL-6, C/EBP beta) expression and hepatocyte proliferation are mutually exclusive. In addition to transactivating liver-specific genes, LAP, but not C/EBP alpha, arrests the cell cycle before the G(1)/S boundary in hepatoma cells. LIP, a liver-inhibitory protein, which is translated from LAP mRNA lacking the activation domain of LAP, is not only ineffective in blocking hepatoma cell proliferation but also antagonizes the effect of LAP on the cell cycle. Deletion analysis indicated that this effect of LIP required only the DNA-binding and leucine zipper domains. In addition we found that integrity of the LAP dimerization and activation domains is indispensable for the arrest of cell proliferation induced by LAP. Thus, hepatocyte differentiation and its characteristic quiescent state may be modulated by the LAP/LIP ratio.