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Transforming growth factor-{beta}1 induces Smad3-dependent {beta}1 integrin gene expression in epithelial-to-mesenchymal transition during chronic tubulointerstitial fibrosis.

ABSTRACT: Transforming growth factor-?1 (TGF-?1)-induced epithelial-to-mesenchymal transition (EMT) contributes to the pathophysiological development of kidney fibrosis. Although it was reported that TGF-?1 enhances ?(1) integrin levels in NMuMG cells, the detailed molecular mechanisms underlying TGF-?1-induced ?(1) integrin gene expression and the role of ?(1) integrin during EMT in the renal system are still unclear. In this study, we examined the role of ?(1) integrin in TGF-?1-induced EMT both in vitro and in vivo. TGF-?1-induced augmentation of ?(1) integrin expression was required for EMT in several epithelial cell lines, and knockdown of Smad3 inhibited TGF-?1-induced augmentation of ?(1) integrin. TGF-?1 triggered ?(1) integrin gene promoter activity as assessed by luciferase activity assay. Both knockdown of Smad3 and mutation of the Smad-binding element to block binding to the ?(1) integrin promoter markedly reduced TGF-?1-induced ?(1) integrin promoter activity. Chromatin immunoprecipitation assay showed that TGF-?1 enhanced Smad3 binding to the ?(1) integrin promoter. Furthermore, induction of unilateral ureteral obstruction triggered increases of ?(1) integrin in both renal epithelial and interstitial cells. In human kidney with chronic tubulointerstitial fibrosis, we also found a concomitant increase of ?(1) integrin and ?-smooth muscle actin in tubule epithelia. Blockade of ?(1) integrin signaling dampened the progression of fibrosis. Taken together, ?(1) integrin mediates EMT and subsequent tubulointerstitutial fibrosis, suggesting that inhibition of ?(1) integrin is a possible therapeutic target for prevention of renal fibrosis.

SUBMITTER: Yeh YC

PROVIDER: S-EPMC2947271 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Transforming growth factor-{beta}1 induces Smad3-dependent {beta}1 integrin gene expression in epithelial-to-mesenchymal transition during chronic tubulointerstitial fibrosis.

Yeh Yi-Chun YC Wei Wei-Chun WC Wang Yang-Kao YK Lin Shih-Chieh SC Sung Junne-Ming JM Tang Ming-Jer MJ

The American journal of pathology 20100813 4

Transforming growth factor-β1 (TGF-β1)-induced epithelial-to-mesenchymal transition (EMT) contributes to the pathophysiological development of kidney fibrosis. Although it was reported that TGF-β1 enhances β(1) integrin levels in NMuMG cells, the detailed molecular mechanisms underlying TGF-β1-induced β(1) integrin gene expression and the role of β(1) integrin during EMT in the renal system are still unclear. In this study, we examined the role of β(1) integrin in TGF-β1-induced EMT both in vitr ...[more]

PMID: 20709799

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Project description:Transforming growth factor (TGF)-beta suppresses breast cancer formation by preventing cell cycle progression in mammary epithelial cells (MECs). During the course of mammary tumorigenesis, genetic and epigenetic changes negate the cytostatic actions of TGF-beta, thus enabling TGF-beta to promote the acquisition and development of metastatic phenotypes. The molecular mechanisms underlying this conversion of TGF-beta function remain poorly understood but may involve signaling inputs from integrins.beta3 Integrin expression or function in MECs was manipulated by retroviral transduction of active or inactive beta3 integrins, or by transient transfection of small interfering RNA (siRNA) against beta3 integrin. Altered proliferation, invasion, and epithelial-mesenchymal transition (EMT) stimulated by TGF-beta in control and beta3 integrin manipulated MECs was determined. Src involvement in beta3 integrin mediated alterations in TGF-beta signaling was assessed by performing Src protein kinase assays, and by interdicting Src function pharmacologically and genetically.TGF-beta stimulation induced alphavbeta3 integrin expression in a manner that coincided with EMT in MECs. Introduction of siRNA against beta3 integrin blocked its induction by TGF-beta and prevented TGF-beta stimulation of EMT in MECs. beta3 integrin interacted physically with the TGF-beta receptor (TbetaR) type II, thereby enhancing TGF-beta stimulation of mitogen-activated protein kinases (MAPKs), and of Smad2/3-mediated gene transcription in MECs. Formation of beta3 integrin:TbetaR-II complexes blocked TGF-beta mediated growth arrest and increased TGF-beta mediated invasion and EMT. Dual beta3 integrin:TbetaR-II activation induced tyrosine phosphorylation of TbetaR-II, a phosphotransferase reaction mediated by Src in vitro. Inhibiting Src activity in MECs prevented the ability of beta3 integrin to induce TbetaR-II tyrosine phosphorylation, MAPK activation, and EMT stimulated by TGF-beta. Lastly, wild-type and D119A beta3 integrin expression enhanced and abolished, respectively, TGF-beta stimulation of invasion in human breast cancer cells.We show that beta3 integrin alters TGF-beta signaling in MECs via Src-mediated TbetaR-II tyrosine phosphorylation, which significantly enhanced the ability of TGF-beta to induce EMT and invasion. Our findings suggest that beta3 integrin interdiction strategies may represent an innovative approach to re-establishing TGF-beta mediated tumor suppression in progressing human breast cancers.

Dataset Information

Transforming growth factor-{beta}1 induces Smad3-dependent {beta}1 integrin gene expression in epithelial-to-mesenchymal transition during chronic tubulointerstitial fibrosis.

Publications

Transforming growth factor-{beta}1 induces Smad3-dependent {beta}1 integrin gene expression in epithelial-to-mesenchymal transition during chronic tubulointerstitial fibrosis.

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