Induction of human LTBP-3 promoter activity by TGF-β1 is mediated by Smad3/4 and AP-1 binding elements
- 作者：Anna K. Kantola ; Jorma Keski-Oja and Katri Koli
- 关键词：LTBP ; TGF-β ; Smad3/4 ; AP-1 ; Osteosarcoma
- 刊名：Gene
- 出版年：2005
- 期刊代码：73_03781119
- 类别：bio
- 出版时间：19 December 2005
- 卷：363
- 期：Complete
- 页码：142-150
- 文件大小：495 K
摘要
Latent TGF-β binding proteins (LTBPs) are extracellular matrix glycoproteins, which are essential for the targeting and activation of TGF-βs. LTBP-3 regulates the bioavailability of TGF-β especially in the bone. To understand the regulation of LTBP-3 expression, we have isolated and characterized the promoter region of human LTBP-3 gene. The GC-rich TATA-less promoter contained several transcription initiation sites and putative binding sites for multiple sequence specific transcription factors including Sp1, AP-1, c-Ets, MZF-1, Runx1 and members of the GATA-family. Reporter gene analyses of the promoter indicated that it was more active in MG-63 than in Saos-2 osteosarcoma cells, suggesting that it is regulated as the endogenous gene. TGF-β1 stimulated the transcriptional activity of LTBP-3 promoter in MG-63 cells, while certain other bone-derived growth factors and hormones were ineffective. TGF-β1 increased LTBP-3 mRNA levels accordingly. Analyses of deletion constructs of the promoter and mutational deletion of specific transcription factor binding sites indicated that Smad3/4 and AP-1 binding sites mediated the TGF-β1 response. The involvement of AP-1 activity was further indicated by decreased TGF-β responsiveness of the LTBP-3 promoter in the presence of a MEK/Erk signaling pathway inhibitor. Our results suggest an important new role for TGF-β1 in the regulation of its binding protein, LTBP-3.