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J. Biol. Chem., Vol. 282, Issue 8, 5661-5669, February 23, 2007

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Convergence of p53 and Transforming Growth Factor (TGF) Signaling on Activating Expression of the Tumor Suppressor Gene maspin in Mammary Epithelial Cells^*

Shizhen Emily Wang, Archana Narasanna^¶, Corbin W. Whitell^||**, Frederick Y. Wu^¶, David B. Friedman^||**, and Carlos L. Arteaga^¶1

From the Departments of Cancer Biology, ^¶Medicine, and ^||Biochemistry, ^**Mass Spectrometry Research Center, Breast Cancer Research Program, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Using two-dimensional difference gel electrophoresis, we identified the tumor suppressor gene maspin as a transforming growth factor (TGF) target gene in human mammary epithelial cells. TGF up-regulatesMaspin expression both at the RNA and protein levels. This up-regulation required Smad2/3 function and intact p53-binding elements in the Maspin promoter. DNA affinity immunoblot and chromatin immunoprecipitation revealed the presence of both Smads and p53 at the Maspin promoter in TGF-treated cells, suggesting that both transcription factors cooperate to induce Maspin transcription. TGF did not activate Maspin-luciferase reporter in p53-mutant MDA-MB-231 breast cancer cells, which exhibit methylation of the endogenous Maspin promoter. Expression of ectopic p53, however, restored ligand-induced association of Smad2/3 with a transfected Maspin promoter. Stable transfection of Maspin inhibited basal and TGF-stimulated MDA-MB-231 cell motility. Finally, knockdown of endogenous Maspin in p53 wild-type MCF10A/HER2 cells enhanced basal and TGF-stimulated motility. Taken together, these data support cooperation between the p53 and TGF tumor suppressor pathways in the induction of Maspin expression, thus leading to inhibition of cell migration.

Received for publication, September 5, 2006 , and in revised form, January 3, 2007.

^* This work was supported by National Institutes of Health R01 Grants CA62212 and CA80195 (to C. L. A.), Breast Cancer Specialized Program of Research Excellence (SPORE) Grant P50 CA98131, and Vanderbilt-Ingram Comprehensive Cancer Center Support Grant P30 CA68485. 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.

¹ To whom correspondence should be addressed: Division of Oncology, Vanderbilt University School of Medicine, 2220 Pierce Ave., 777 PRB, Nashville, TN 37232-6307. Tel.: 615-936-3524; Fax: 615-936-1790; E-mail: carlos.arteaga{at}vanderbilt.edu.

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