Regulation of Epidermal Bullous Pemphigoid Antigen 1 (BPAG1) synthesis by homeoprotein transcription factors

Gaëll Mainguy, Henrik Ernø, María Luz Montesinos, Brigitte Lesaffre, Wolfgang Wurst, Michel Volovitch, Alain Prochiantz

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

In a recent gene-trap screen, we identified the gene coding for Epidermal Bullous Pemphigoid Antigen 1 (BPAG1) as a putative transcriptional target of Engrailed and of other homeoproteins with a glutamine in position 50 of their homeodomain. We now show that the nuclear addressing of the homeodomains of Engrailed (EnHD) and Antennapedia (AntpHD) upregulates BPAG1e transcription in immortalized human keratinocytes (GMA24FIA) expressing En1. This upregulation is not observed with AntpHD-Q50A, a variant of AntpHD in which a single mutation abolishes its high-affinity binding to target DNA, thus strongly suggesting that BPAG1e upregulation homeodomains reflects their specific recognition of homeoprotein-binding sites in the BPAG1e locus. This is further confirmed by DNase I footprinting and electrophoretic mobility shift assays that reveal, within the cloned BPAG1e promoter, several sites of direct interaction with EnHD and Engrailed. Co-transfection experiments in GMA24FIA human keratinocytes, COS-7 simian fibroblasts, and CHP-100 human neuroepithelial cells show that Engrailed, Hoxa-5, and Hoxc-8 regulate BPAG1e promoter activity and that this regulation is context-dependent. Finally, using a mouse line with LacZ inserted within the En1 locus, we identify the keratinocytes of the ventral paws, including the epithelial cells of the eccrine tubules, as a strong site of En1 expression throughout adulthood. We therefore propose that BPAG1e, a 230 kDa keratin-binding protein expressed in keratinocytes and participating in the maintenance of hemidesmosomes at the dermis-epidermis border, is directly regulated by homeoprotein transcription factors.

Original languageEnglish
Pages (from-to)643-650
Number of pages8
JournalJournal of Investigative Dermatology
Volume113
Issue number4
DOIs
StatePublished - 1999
Externally publishedYes

Keywords

  • BPAG1
  • Engrailed
  • Hemidesmosomes
  • Homeoproteins
  • Keratinocytes

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