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J Biol Chem, Vol. 275, Issue 15, 11320-11326, April 14, 2000
From the Department of Medicine, Albert Einstein College of
Medicine, Bronx, New York 10461
Smad7 is an inducible intracellular inhibitor of
transforming growth factor-
Smad3 and Smad4 Mediate Transcriptional Activation of the Human
Smad7 Promoter by Transforming Growth Factor
*
,
(TGF-) signaling that is regulated by
diverse stimuli including members of the TGF- superfamily. To define the molecular mechanisms of negative control of TGF- signaling, we
have isolated the human SMAD7 gene and characterized its
promoter region. A 
303 to +672 SMAD7 region contained a
palindromic GTCTAGAC Smad binding element (SBE) between nucleotides
179 and 172 that was necessary for the induction of a Smad7
promoter luciferase reporter gene by TGF-. Electrophoretic mobility
shift assays using oligonucleotide probes demonstrated that TGF-
rapidly induced the binding of an endogenous SBE-binding complex (SBC)
containing Smad2, Smad3, and Smad4. Transfection assays in mouse
embryonic fibroblasts (MEFs), with targeted deletions of either Smad2
or Smad3, and the Smad4-deficient cell line MD-MBA-468 revealed that both Smad3 and Smad4, but not Smad2, were absolutely required for
induction of the Smad7 promoter reporter gene by TGF-. Furthermore, the TGF--inducible SBE-binding complex was diminished in
Smad2-deficient MEFs when compared with wild type MEFs and not
detectable in Smad3-deficient MEFs and MD-MBA-468 cells. Taken
together, our data demonstrate that TGF- induces transcription of
the human SMAD7 gene through activation of Smad3 and Smad4
transcription factor binding to its proximal promoter.
*
This work was supported by American Heart Association
Grant-in-aid 9950349N and by National Institutes of Health Grant
DK-56077-01 (to E. P. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of the National Kidney Foundation/Kevin and Gloria Keily
Fellow research fellowship award. Parts of this work are presented in
fulfillment of the requirements for the MD. degree at the Ludwig
Maximilian University of Munich School of Medicine, Munich, Germany.
§
To whom correspondence should be addressed: Division of Nephrology,
Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY
10461. Tel.: 718-430-3158; Fax: 718-430-8963; E-mail:
bottinge@aecom.yu.edu.
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