Cloning and Characterization of the Human β4-Integrin Gene Promoter and Enhancers

Abstract

The cell-surface adhesion molecule ␣ 6 ␤ 4 -integrin is a receptor for laminins and a component of hemidesmosomes. ␤ 4 -Integrin expression is restricted to proliferating basal keratinocytes in the epidermis and is suppressed when differentiation commences. Altered ␤ 4 -integrin expression levels correlate significantly with the aggressive behavior of cancers. In order to clarify the mechanisms that regulate transcription of the ␤ 4 -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 ␤ 4 -integrin gene expression in processes such as cell growth and differentiation, apoptosis, and cancer development and metastasis.

Regulation of β4-integrin expression by epigenetic modifications in the mammary gland and during the epithelial-to-mesenchymal transition

“…1A). In pursuit of a mechanism to account for this differential localization, we observed that the proximal promoter region of the mouse β4 gene (Takaoka et al, 1998) contains a CpG island that extends into the first exon (Fig. 1C).…”

“…Interestingly, a high GC content in the β4 promoter was observed in its original cloning 10 years ago, but the possibility of epigenetic regulation was not pursued (Takaoka et al, 1998). We were struck by the presence of a large CpG island in our analysis of this promoter, an observation that provided the impetus for this study.…”

Transcription of the Transforming Growth Factor β Activating Integrin β8 Subunit Is Regulated by SP3, AP-1, and the p38 Pathway

“…Promoter studies of other integrins, such as ␣2, ␣3, ␣5, ␣6, ␣11, ␣IIb, ␤4, ␤5, CD11␤-␦, and CD18, have shown requirements for Sp1/Sp3 and/or AP-1 transcription factors and their cognate sites for expression (55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(77)(78)(79). In particular, the promoter of ITGAV (integrin ␣v), the gene that encodes the heterodimerization partner of integrin ␤8, is also regulated by Sp1 and Sp3 (65).…”

Cell-Extracellular Matrix Interactions in Normal and Diseased Skin

“…There have been relatively few attempts to understand how epidermal integrin and ECM gene expression is regulated at the transcriptional level (Corbi et al 2000;Turner et al 2006;Takaoka et al 1998). However, one aspect that has been explored is negative regulation of integrin, cytoskeleton, and ECM genes by Myc Berta et al 2010).…”