KGF promotes integrin α₅ expression through CCAAT/enhancer-binding protein-β

Keratinocyte growth factor (KGF) and α₅β₁- integrin are not expressed in normal skin but they are both highly upregulated in the migrating epidermis during wound healing. Here we report that KGF increased α₅ mRNA and protein levels in epidermoid carcinoma cells and stratified bioengineered epidermis. Interestingly, KGF increased integrin α₅ in the basal as well as suprabasal cell epidermal layers. Promoter studies indicated that KGF-induced integrin α₅ promoter activation was dependent on the C/EBP transcription factor binding site. Accordingly, KGF induced sustained phosphorylation of C/EBP-β that was dependent on activation of ERK1/2. In addition, a dominant negative form of C/EBP-β inhibited α₅ promoter activity and blocking C/EBP-β with siRNA diminished integrin α₅ expression. Taken together, our data indicate that KGF increased integrin α₅ expression by phosphorylating C/EBP-β. Interestingly, KGF-induced upregulation of integrin α₅ was more pronounced in three-dimensional tissue analogues than in conventional two-dimensional culture suggesting that stratified epidermis may be useful in understanding the effects of growth factors in the local tissue microenvironment.