A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene

作者：Grotendorst GR^*; Okochi H; Hayashi N

来源：Cell Growth and Differentiation, 1996, 7(4): 469-480.

We reported previously that transforming growth factor beta (TGF-beta) selectively induced high levels of connective tissue growth factor (CTGF) mRNA and protein in human skin fibroblasts. In this study, we investigated the molecular mechanism for TGF-beta regulation of CTGF gene expression, Northern blot and run-on transcription assays indicate that TGF-beta directly activates transcription of the CTGF gene, Fragments of the 5' flanking region of the human CTGF gene were linked to luciferase reporter constructs, TGF-beta induced a 25-30-fold increase in luciferase activity in NIH/3T3 fibroblasts that had been transfected with this construct compared with nontreated cells after 24 h incubation. Other growth factors, such as platelet-derived growth factor or fibroblast growth factor, caused only a 2-3-fold induction, This response to TGF-beta occurred only in human skin fibroblasts, fetal bovine aortic smooth muscle cells, and NIH/3T3 fibroblasts but not in the epithelial cell lines tested, Analysis of deletion mutants indicated that an important TGF-beta regulatory element is located between positions -162 and -128 of the CTGF promoter sequence. A fragment of the promoter containing this region conferred TGF-beta induction to a SV40 enhancerless promoter. Methylation interference and competition gel shift assays mapped a unique 13-nucleotide sequence delineating a novel TGF-beta cis-regulatory element, Point mutations in this region result in a complete loss of the TGF-beta induction, identifying this sequence as a new TGF-beta response element.

• 出版日期1996-4