C EBP-BETA/LAP CONTROLS DOWN-REGULATION OF ALBUMIN GENE-TRANSCRIPTIONDURING LIVER-REGENERATION/

Expression of the albumin gene in the liver is controlled by several l iver-enriched transcription factors. However, the mechanisms which con tribute to its regulation during pathophysiological states, such as li ver regeneration, are still little understood. In the present study we found that during liver regeneration downregulation of albumin mRNA e xpression is transcriptionally controlled through a minimal element (n ucleotide -170 to +22) of the albumin promoter and is observed mainly during the G(1) phase of the cell cycle, while high levels of albumin expression are preserved at later time points, Decreased albumin mRNA levels correlate with a dramatic increase in nuclear expression of C/E BP-beta/LAP, a protein known to bind to the D site of the albumin prom oter and also to be involved in cell cycle control. In contrast, nucle ar expression of other factors such as HNF-1 or C/EBP-alpha, which als o have been shown to transcriptionally control albumin expression, is either unchanged or slightly decreased. We show that pre- and post-tra nslational mechanisms are involved in the higher nuclear expression of C/EBP-beta/LAP as early as 1 h after hepatectomy, which also leads to ifs increased binding toward the D site of the albumin promoter. Fina lly, in vitro transcription assays with liver nuclear extracts and rec ombinant C/EBP-beta/LAP demonstrate that C/EBP-beta/LAP can directly d own-regulate transcription mediated by the minimal element of the albu min promoter. Additionally the inhibitory role of C/EBP-beta/LAP on th e albumin minimal promoter could be confirmed by transfection experime nts in hepatoma cells. These results indicate that C/EBP-beta/LAP, whi le enhancing transcription of cell cycle-related genes and controlling G(1)/S phase checkpoint, down-regulates a major liver function, i.e. albumin synthesis, to prepare the hepatocyte for entry into the cell c ycle.