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J. Biol. Chem., Vol. 275, Issue 22, 16979-16985, June 2, 2000
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From the Departments of Growth and Development and Anatomy,
Programs in Cell Biology and Developmental Biology, University of
California at San Francisco,
San Francisco, California 94143-0640
Smads regulate transcription of defined genes in
response to transforming growth factor-
Transcriptional Regulation of the Transforming Growth
Factor-
-inducible Mouse Germ Line Ig 
Constant Region Gene by
Functional Cooperation of Smad, CREB, and AML Family Members*
(TGF-) receptor
activation. This process involves functional cross-talk of Smads with
transcription factors at responsive DNA elements to achieve maximal
transcription activation and specificity. TGF- has been shown to
induce transcription of the germ line (GL) Ig 
constant region gene
and to direct class switching to IgA antibodies. It has been shown that
acute myeloid leukemia (AML) transcription factors cooperate with Smad3 to stimulate transcription from the GL Ig constant region gene promoter. We report here that the TGF--induced transcription from
this promoter requires DNA binding of cAMP-response element-binding protein (CREB) to the nearby ATF/cAMP-response element site and of
Smads to a nearby Smad binding sequence. At these sites, Smad3/4 cooperates with CREB to activate transcription in response to TGF-,
and disruption of either binding sequence abolished TGF--induced transcription. In addition, AML1 or AML2 also binds to the promoter and
cooperates with Smad3/4, and in this way further enhances the
TGF--induced transcriptional activation of the GL Ig promoter. Thus, whereas Smad3/4, CREB, and AML family members bind independently to the respective DNA sequences in the GL Ig promoter, functional synergy of Smads with CREB and AML proteins results in maximal TGF--induced transcription.
*
This research was supported by National Institutes of Health
Grant CA63101 (to R. D.) and a postdoctoral fellowship from American Lung Association (to Y. Z.).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.
To whom correspondence should be addressed: Dept. of Growth and
Development, University of California at San Francisco, San Francisco,
CA 94143-0640. Tel.: 415-476-7322; Fax: 415-476-1499; E-mail:
derynck@itsa.ucsf.edu.
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