Transcriptional induction of the alpha-1 acid glycoprotein (AGP) gene by synergistic interaction of two alternative activator forms of AGP/enhancer-binding protein (C/EBP beta) and NF-kappaB or Nopp140

Abstract

Alpha-1 acid glycoprotein/enhancer-binding protein (AGP/EBP) (C/EBPbeta), a member of the C/EBP family, is one of the key transcription factors responsible for the induction of a wide array of genes, some of which are expressed during the acute-phase response. Both activator and repressor were shown to be encoded by the intronless agp/ebp or its rat and human homologs, which contain a common bZIP domain at their C-terminal regions. Expression of the AGP gene (agp) is regulated by AGP/EBP in liver during the acute-phase response. However, the molecular mechanism for this regulation is poorly understood. The experiments reported here demonstrate that two activator forms of AGP/EBP, one of which has an additional 21 amino acids at its N-terminal region, are expressed in liver as well as in a number of cell lines. We have also demonstrated that NF-kappaB and a phosphoprotein of 140 kDa, Nopp140, interact with different AGP/EBP activators synergistically, which results in induction of the agp gene in an AGP/EBP-binding-motif-dependent manner. Furthermore, extracellular stimuli that are known to be NF-kappaB inducers can selectively activate the agp gene by cooperating with one of the two activator forms of AGP/EBP. The physiological significance of differential regulation for the function of two activator forms of AGP/EBP through selective interaction with different transcription factors is discussed.