Cloning and characterization of the human β₄-integrin gene promoter and enhancers

The cell-surface adhesion molecule α₆β₄-integrin is a receptor for laminins and a component of hemidesmosomes. β₄-Integrin expression is restricted to proliferating basal keratinocytes in the epidermis and is suppressed when differentiation commences. Altered β₄-integrin expression levels correlate significantly with the aggressive behavior of cancers. In order to clarify the mechanisms that regulate transcription of the β₄- integrin gene, we cloned its 5'-flanking region. This 5'-flanking region was found to have a high G + C content and not to contain either TATA or CAAT boxes. Nested delimitation and reporter analyses mapped a basal promoter to nucleotides -106 to +105, surrounding the most proximal transcription initiation site. Gel retardation and mutational analyses revealed that cooperation between AP1 and Ets, interacting with other factors, mediated the promoter activity. In addition to the promoter element, enhancer activity was found in the first intron (+1905/+3933) and in a sequence upstream of the promoter region (-414/-107). These findings should facilitate our understanding of the regulation of β₄-integrin gene expression in processes such as cell growth and differentiation, apoptosis, and cancer development and metastasis.