Identification of HTF (HER2 transcription factor) as an AP-2 (activator protein-2) transcription factor and contribution of the HTF binding site to ERBB2 gene overexpression

Douglas Vernimmen, Dominique Begon, Christophe Salvador, Stéphanie Gofflot, Madeleine Grooteclaes, Rosita Winkler

Research output: Contribution to journalArticlepeer-review

Abstract

The ERBB2 gene is overexpressed in 30% of human breast cancers and this is correlated with poor prognosis. Overexpression of the ERBB2 gene is due to increased transcription and gene amplification. Our previous studies have identified a new cis element in the ERBB2 promoter which is involved in the gene's overexpression. This cis element, located 501 bp upstream from the main ERBB2 transcription initiation site, binds a transcription factor called HTF (HER2 transcription factor). We report here the identification of HTF as an AP-2 (activator protein-2) transcription factor. The new cis element is bound by AP-2 with high affinity, compared with a previously described AP-2 binding site located 284 bp downstream. Co-transfection of an AP-2alpha expression vector with a reporter vector containing the newly identified AP-2 binding site in front of a minimal ERBB2 promoter induced a dose-dependent increase in transcriptional activity. We examined the contribution of the new AP-2 binding site to ERBB2 overexpression. For this purpose we abolished the new and/or the previously described AP-2 binding sequence by site-directed mutagenesis. The results show that the two functional AP-2 sites in the first 700 bp of the ERBB2 promoter co-operate to achieve maximal transcriptional activity.
Original languageEnglish
Pages (from-to)323-9
Number of pages7
JournalBiochemical Journal
Volume370
Issue numberPt 1
DOIs
Publication statusPublished - 2003

Keywords

  • AP-2 binding site
  • ERBB2 promoter
  • HER2 transcription factor
  • HTF
  • human
  • transcription regulation

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