Characterization of the c-Myb-responsive Region and Regulation of the Human Type I Collagen alpha 2 Chain Gene by c-Myb

Research output: Contribution to journalArticle

Authors

  • MM Lucetti
  • P Paroncini
  • P Majlingova
  • M Mucenski
  • S Svegliati Baroni
  • P Sambo
  • J Golay
  • M Introna
  • A Gabrielli

Abstract

We have characterized the role of c-Myb and B-Myb in the regulation of human type I collagen alpha2 chain gene expression in fibroblastic cells. We have identified four Myb-binding sites (MBSs) in the promoter. Transactivation assays on wild type and mutant promoter-reporter constructs demonstrated that c-Myb, but not B-Myb, can transactivate the human type I collagen alpha 2 chain gene promoter via the MBS-containing region. Electrophoretic mobility shift assay experiments showed that c-Myb specifically binds to each of the four MBS; however, the mutagenesis of site MBS-4 completely inhibited transactivation by c-Myb, at least in the full-length promoter. In agreement with these results, c-myb(-/-) mouse embryo fibroblasts (MEFs) showed a selective lack of expression of type I collagen alpha 2 chain gene but maintained the expression of fibronectin and type III collagen. Furthermore, transforming growth factor-beta induced type I collagen alpha 2 chain gene expression in c-myb(-/-) MEFs, implying that the transforming growth factor-beta signaling pathway is maintained and that the absence of COL1A2 gene expression in c-myb(-/-) MEFs is a direct consequence of the lack of c-Myb. The demonstration of the importance of c-Myb in the regulation of the type I collagen alpha 2 chain gene suggests that uncontrolled expression of c-Myb could be an underlying mechanism in the pathogenesis of several fibrotic disorders.

Details

Original languageEnglish
Pages (from-to)1533-1541
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number3
Early online date6 Nov 2002
Publication statusPublished - 10 Jan 2003