Synergistic trans-activation of the human C-reactive protein promoter by transcription factor HNF-1 binding at two distinct sites

Carlo Toniatti, Anna Demartis, Paolo Monaci, Alfredo Nicosia, Gennaro Ciliberto

Research output: Contribution to journalArticlepeer-review

Abstract

The promoter region of the human C-reactive protein (CRP) gene comprises two distinct regions (APREs, for Acute Phase Responsive Elements) each one containing information necessary and sufficient for liver specific and IL-6 inducible expression in human hepatoma Hep3B cells. In this paper we show that both APREs contain a low affinity binding site for the liver specific transcription factor HNF-1/LF-B1. The two sites are separated by ∼80 bp. Mutations in either of the two sites abolish inducible expression. The same effect is specifically obtained in cotransfection competition experiments when the human albumin HNF-1 site is used as competitor. However, HNF-1 is not the intranuclear mediator of IL-6 because synthetic promoters formed by multimerized copies of different HNF-1 binding sites are not transcriptionally activated by this cytokine. An expression vector encoding full length HNF-1 is capable of trans-activating transcription from the wild-type CRP promoter but not from mutants which have lost the ability to bind HNF-1. Moreover, the level of trans-activation observed with the natural promoter containing both HNF-1 binding sites is far greater than the level of mutated variants containing only one of the two sites. This result strongly suggests that two HNF-1 molecules bound simultaneously to sites distant from each other can act synergistically to activate gene expression.

Original languageEnglish
Pages (from-to)4467-4475
Number of pages9
JournalEMBO Journal
Volume9
Issue number13
Publication statusPublished - 1990

Keywords

  • C-reactive protein
  • Liver specific gene expression transcription factor HNF-1
  • Trans-activation

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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