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Differential Binding of the Transcription Factors Sp1, AP-1, and NFI to the Promoter of the Human 5 Integrin Gene Dictates Its Transcriptional Activity

¹From the Oncology and Molecular Endocrinology Research Center, and ⁵Unité de Recherche en Ophtalmologie, Centre de Recherche du CHUL-CHUQ, Québec, Canada; ⁴Départements de Chirurgie and ⁶Anatomie-Physiologie, Université Laval, Québec, Canada; ²Service of Genetics, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada; and ³Laboratoire d’Organogénèse Expérimentale (LOEX), Hôpital du Saint-Sacrement du CHA, Québec, Canada.

PURPOSE. Damage to the corneal epithelium results in the massive secretion of fibronectin (FN) shortly after injury and induces the expression of its integrin receptor 5β1. The authors reported previously that FN induces 5 expression in human corneal epithelial cells and rabbit corneal epithelial cells by altering the binding of the transcription factor (TF) Sp1 to a regulatory element from the 5 promoter that it is also flanked by binding sites for the TFs NFI and AP-1. Here, they assessed the function of NFI and AP-1 on 5 gene expression and evaluated the contribution of FN to their overall regulatory influence.

METHODS. TF binding to the 5 promoter was evaluated in vitro by electrophoretic mobility shift assays and in vivo by ligation-mediated PCR or chromatin immunoprecipitation. TFs expression was monitored by Western blot, whereas their influence was assessed by transfection and RNAi analyses.

RESULTS. Coexpression of Sp1, NFI, and AP-1 was demonstrated in all cell types, and each TF was shown to bind efficiently to the 5 promoter. Whereas both AP-1 and Sp1 activated expression directed by the 5 promoter, NFI functioned as a potent repressor of that gene. Interestingly, FN could either promote or repress 5 promoter activity in a cell density–dependent manner by differentially altering the ratio of these TFs.

CONCLUSIONS. These results suggest that 5 gene expression is likely dictated by subtle alterations in the nuclear ratio of TFs that either repress (NFI) or activate (Sp1 and AP-1) 5 transcription in corneal epithelial cells.

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