Characterization of the transcriptional signature of C/EBPbeta isoforms (LAP/LIP) in Hep3B cells: implication of LIP in pro-survival functions

J Hepatol. 2011 Jun;54(6):1185-94. doi: 10.1016/j.jhep.2010.09.021. Epub 2010 Oct 31.


Background & aims: C/EBPbeta is an important mediator of several cellular processes, such as differentiation, proliferation, and survival of hepatic cells. However, a complete catalog of the targets of C/EBPbeta or the mechanism by which this transcription factor regulates certain liver-dependent pathways has not been clearly determined. Two major natural isoforms of this transcription factor exist: the liver-enriched activating protein (LAP) and the liver-enriched inhibitory protein (LIP), a functional LAP antagonist. In this study, we used the opposing transcriptional effects driven by LAP and LIP to determine the genuine C/EBPbeta molecular signature in the Hep3B human hepatoma cell line. We subsequently investigated the role of each of the LAP and LIP isoforms in drug-induced Hep3B cell death.

Methods: We engineered Hep3B cells with regulated LAP or LIP expression using the Tet-off expression system. The genes that showed inverse regulation by LAP and LIP were identified by cDNA array analysis. The cohort of direct-C/EBPbeta-targets was distinguished from indirect-targets by ChIP-on-chip analysis.

Results: We characterized 676 genes by this approach. Among these genes, 39 are novel direct targets of C/EBPbeta. Eleven of these new direct targets are involved in cell survival, suggesting critical roles for LAP/LIP isoforms in this cellular process. Therefore, we examined the effects of LAP and LIP over-expression on cell survival. We show that LIP promotes survival in staurosporine- or taxol-induced Hep3B cell death.

Conclusions: Our study provides new molecular and cellular insights into the role of C/EBPbeta in cells of hepatic origin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CCAAT-Enhancer-Binding Protein-beta / genetics*
  • CCAAT-Enhancer-Binding Protein-beta / physiology
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology
  • Cell Death / drug effects
  • Cell Death / genetics
  • Cell Death / physiology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Gene Expression Profiling
  • Genetic Engineering
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Models, Biological
  • Oligonucleotide Array Sequence Analysis
  • Paclitaxel / pharmacology
  • Protein Isoforms / genetics
  • Protein Isoforms / physiology
  • Staurosporine / pharmacology
  • Transcription, Genetic


  • CCAAT-Enhancer-Binding Protein-beta
  • Protein Isoforms
  • Staurosporine
  • Paclitaxel