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J. Biol. Chem., Vol. 278, Issue 44, 43001-43007, October 31, 2003
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Transforming Growth Factor-
-induced Apoptosis Is Mediated by Smad-dependent Expression of GADD45b through p38 Activation*
**
From the
Laboratory of Cell Regulation and Carcinogenesis and the Basic Research Laboratory, NCI, National Institutes of Health, Bethesda, Maryland 20892-5055, the ¶Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, and the ||Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461
Transforming growth factor-
(TGF-)-dependent apoptosis is important in the elimination of damaged or abnormal cells from normal tissues in vivo. In this report, we identify GADD45b as an effector of TGF--induced apoptosis. GADD45b has been shown to be a positive mediator of apoptosis induced by certain cytokines and oncogenes. We show that Gadd45b is an immediateearly response gene for TGF- and that the proximal Gadd45b promoter is activated by TGF- through the action of Smad2, Smad3, and Smad4. We show that ectopic expression of GADD45b in AML12 murine hepatocytes is sufficient to activate p38 and to trigger apoptotic cell death, whereas antisense inhibition of Gadd45b expression blocks TGF--dependent p38 activation and apoptosis. Furthermore, we also show that TGF- can activate p38 and induce apoptosis in mouse primary hepatocytes from wild-type mice, but not from Gadd45b–/– mice. All of these findings suggest that GADD45b participates in TGF--induced apoptosis by acting upstream of p38 activation.
Received for publication, July 21, 2003 , and in revised form, August 19, 2003.
* The costs of publication of this article were defrayed in part by the payment of page charges. This 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: Lab. of Cell Regulation and Carcinogenesis, NCI, NIH, Bldg. 41, Rm. C629, 41 Library Dr., MSC 5055, Bethesda, MD 20892-5055. Tel.: 301-496-5391; Fax: 301-496-8395; E-mail: robertsa{at}dce41.nci.nih.gov.
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