Nucleic Acids Research, 2003, Vol. 31, No. 4 1302-1310
© 2003 Oxford University Press
Smad proteins regulate transcriptional induction of the SM22
gene by TGF-ß
Department of Cell Biology, Georgetown University Medical Center, Box 571436, Washington, DC 20057-1436, USA
*To whom correpondence may be addressed. Tel: +1 202 687 4381; Fax: +1 202 687 1823; Email: rjl24@georgetown.edu
Smad proteins transduce signals from transforming growth factor-ß (TGF-ß) receptors and regulate transcription of target genes. TGF-ß is implicated in the regulation of the smooth muscle cell specific gene SM22
, but little is known about how Smads are involved in SM22 gene transcription. In this report, we demonstrate that TGF-ß activation of the SM22 promoter is Smad dependent in C3H10T1/2 cells, BALB 3T3 cells and neural crest Monc-1 cells. We find that the promoter region from –162 to +41 is sufficient to up-regulate the reporter gene upon TGF-ß induction. Smad3, Smad1 and Smad4 are found in TGF-ß inducible complexes that bind to a region containing a Smad binding site (SBS) and a medea box. Both the SBS and medea box are necessary for complex formation and are functionally important. Smad4 is limiting for TGF-ß induction, and Smad3, but not Smad1, significantly contributes to maximal activation. Time course luciferase assays and time course gel mobility shift assays reveal that the Smad3/4 complex is largely responsible for the immediate response of the SM22 promoter to TGF-ß induction, and also contributes to the maximal promoter activity. We further demonstrate that AP-1 elements contribute to induction of the SM22 promoter by TGF-ß.
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