Transforming growth factor-β up-regulates the β5 integrin subunit expression via Sp1 and Smad signaling

C. F. Lai, X. Feng, R. Nishimura, S. L. Teitelbaum, L. V. Avioli, F. P. Ross, S. L. Cheng

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

Integrin-mediated cell-matrix interactions play important roles in regulating cell function. Since transforming growth factor-β (TGF-β) modulates many osteoblast activities, we hypothesized that the growth factor acts in part by modulating integrin expression. TGF-β increased cell adhesion to vitronectin and up-regulated the surface level of α(v)β5 via increasing β5 protein synthesis by a transcriptional mechanism. Promoter activity analysis demonstrated that a TGF-β-responsive element resides between nucleotides -63 and -44. Electrophoretic mobility shift assay and immunoprecipitation/Western studies indicated that the nuclear complex formed using the -66/-42 oligonucleotide contained both Sp1/Sp3 and Smad proteins. Since nuclear Sp1/Sp3 levels were not altered, whereas Smad levels were increased by TGF-β, we investigated the roles of Smad proteins in the up-regulation of β5 gene activation. Co-transfection of cells with β5 promoter reporter construct and expression vectors for Smad3, Smad4, and Sp1 increased the stimulatory effect of TGF-β. Furthermore, expression of dominant negative Smad3 or Smad4 in cells decreased or abolished the stimulation of β5 promoter activity by TGF-β. Smad4 mutant also inhibited the up-regulation of surface β5 level by TGF-β. Thus, TGF-β increases expression of the integrin β5 gene by mechanisms involving Sp1/Sp3 and Smad transcription factors.

Original languageEnglish
Pages (from-to)36400-36406
Number of pages7
JournalJournal of Biological Chemistry
Volume275
Issue number46
DOIs
StatePublished - Nov 17 2000

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