Involvement of Sp1 elements in the promoter activity of the alpha1-proteinase inhibitor gene.
The transcripts of the alpha1-proteinase inhibitor in the cornea are different from those in hepatocytes and monocytes, suggesting that alpha1-proteinase inhibitor gene transcription may respond to different cell-specific regulatory mechanisms. Although information on alpha1-proteinase inhibitor gene structure has been obtained, little is known regarding the cis- and trans-acting factors that regulate its expression. In this study, we cloned and sequenced a 2. 7-kilobase 5'-flanking region upstream from the corneal transcription initiation site of the gene, demonstrated functional promoter activity, and identified the regulatory elements. Sequencing revealed that the 5'-flanking element was highly G/C-rich in regions proximal to the corneal transcription start site. DNase I footprinting located 10 potential Sp1-binding sites between nucleotides -1519 and +44. The putative promoter was functional in human corneal stromal cells, but not in human skin, scleral, and conjunctival fibroblasts, suggesting that the promoter may be corneal cell-specific. The promoter activity in the corneal cells was repressed when Sp1 was coexpressed. In the cornea-thinning disease keratoconus, down-regulation of the alpha1-proteinase inhibitor gene and increased Sp1 expression have both been demonstrated. The current results suggest that down-regulation of the inhibitor in keratoconus corneas may be related directly to overexpression of the Sp1 gene. This information may help elucidate the molecular pathways leading to the altered alpha1-proteinase inhibitor expression in keratoconus.[1]References
- Involvement of Sp1 elements in the promoter activity of the alpha1-proteinase inhibitor gene. Li, Y., Zhou, L., Twining, S.S., Sugar, J., Yue, B.Y. J. Biol. Chem. (1998) [Pubmed]
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