RETRACTED: Transactivation of EGF receptor induced by angiotensin II regulates fibronectin and TGF-β gene expression via transcriptional and post-transcriptional mechanisms (Retracted Article. See vol 251, pg 167, 2003)

被引：21

作者：

Matsubara, H ^{[1
]}

Moriguchi, Y ^{[1
]}

Mori, Y ^{[1
]}

Masaki, H ^{[1
]}

Tsutsumi, Y ^{[1
]}

Shibasaki, Y ^{[1
]}

Uchiyama-Tanaka, Y ^{[1
]}

Fujiyama, S ^{[1
]}

Koyama, Y ^{[1
]}

Nose-Fujiyama, A ^{[1
]}

Iba, S ^{[1
]}

Tateishi, E ^{[1
]}

Iwasaka, T ^{[1
]}

机构：

[1] Kansai Med Univ, Dept Med 2, Osaka 5708507, Japan

来源：

MOLECULAR AND CELLULAR BIOCHEMISTRY | 2000年 / 212卷 / 1-2期

关键词：

angiotensin II receptors; angiotensin II type 1 receptor; angiotensin II type 2 receptor; angiotensin II; AT1; receptor; epidermal growth factor receptor;

D O I：

10.1023/A:1007189828584

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The signaling cascade elicited by angiotensin II (Ang II) resembles that characteristic of growth factor, and recent evidence indicates transactivation of epidermal growth factor receptor (EGF-R) by G protein-coupled receptors. Here, we report the involvement of EGF-R in Ang II-induced synthesis of fibronectin and TGF-beta in cardiac fibroblasts. Ang II stimulated fibronectin mRNA levels dose-dependently with a maximal increase (similar to5-fold) observed after 12 h of incubation. Ang II-, or calcium ionophore-induced fibronectin synthesis was completely abolished by tyrosine kinase inhibitors and intracellular Ca2+ chelating agents. Ang II-induced fibronectin mRNA was not affected by PKC inhibitors or PKC depletion, whereas specific inhibition of EGF-R function by a dominant negative EGF-R mutant and tyrphostin AG1478 abolished induction of fibronectin mRNA. We isolated the rat fibronectin gene including the 5'-flanking region and found that the AP-1 binding site present in the promoter region was responsible for the Ang II responsiveness of this gene. Gel retardation assay revealed the binding of nuclear protein to the AP-1 site, which was supershifted with anti-c-fos and anti-c-jun but not anti-ATF-2 antibodies. Conditioned medium from Ang II-treated cells contained TGF-beta bioactivity and addition of neutralizing TGF-beta antibody modestly (46%) inhibited induction of fibronectin. Ang II-induced synthesis of TGF-beta was also abolished by inhibition of EGF-R function. The effect of TGF-beta was exerted by stabilizing fibronectin mRNA without affecting the promoter activity and required de novo protein synthesis. We concluded that Ang II-induced expression of fibronectin and TGF-beta is mediated by downstream signaling of EGF-R transactivated by Ca2+-dependent tyrosine kinase, and that Ang II-induced fibronectin mRNA expression is regulated by two different mechanisms ; transcriptional control by binding of c-fos/c-jun complex to the AP-1 site, and post-transcriptional control by mRNA stabilization due to autocrine and/or paracrine effects of TGF-beta. Thus, this study suggested that the action of Ang II on extracellular matrix formation should be interpreted in association with the EGF-R signaling cascade.

引用

页码：187 / 201

页数：15

共 61 条

[1] Angiotensin II stimulates tyrosine phosphorylation and activation of insulin receptor substrate 1 and protein-tyrosine phosphatase 1D in vascular smooth muscle cells [J].