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J. Biol. Chem., Vol. 281, Issue 33, 23748-23756, August 18, 2006

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The Novel PIAS-like Protein hZimp10 Enhances Smad Transcriptional Activity^*

From the Departments of Urology and Genetics, Stanford University School of Medicine, Stanford, California 94303-5118

Transforming growth factor (TGF-) plays critical roles in the control of cell proliferation, differentiation, and apoptosis. Smad proteins are substrates of the TGF- type I receptor and are responsible for transducing receptor signals to target genes in the nucleus. The PIAS (protein inhibitor of activated STAT) proteins were originally identified as transcriptional co-regulators of the JAK-STAT pathway. Subsequently, cross-talk between the PIAS proteins and other signaling pathways has been shown to be involved in various cellular processes. Importantly, PIAS proteins modulate TGF- signaling by regulating the transcriptional activity of Smad3. In this study we tested whether hZimp10, a novel PIAS-like protein, acts as other PIAS proteins to regulate Smad3-mediated transcription. We show that expression of exogenous hZimp10 enhances the transcriptional activity of Smad3, which appears to be Smad4-dependent and responsive to TGF- induction. Furthermore, knockdown of endogenous hZimp10 reduced the transcriptional activity of Smad3. A protein-protein interaction between Smad3 and Smad4 with hZimp10 was identified in glutathione S-transferase-pulldown and co-immunoprecipitation assays. The Miz domain of hZimp10 and the MH2 domains of Smad3 and Smad4 were mapped as the regions responsible for binding. Results from immunostaining assays further demonstrated that Smad3, Smad4, and hZimp10 co-localize within cell nuclei. Finally, we demonstrated that Smad3/4-mediated transcription is significantly impaired in response to TGF- induction in Zimp10 null (zimp10-/-) embryonic fibroblasts. Taken together, these results provide the first line of evidence to demonstrate a role for Zimp10 in regulating the TGF-/Smad signaling pathway.

Received for publication, July 29, 2005 , and in revised form, June 14, 2006.

^* This work was supported by National Institutes of Health Grants CA070297, CA087767, DK061002, and 5T32 CA09302-27 and Dept. of Army Prostate Cancer Grant DAMD17-03-1-0090. 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 requests for reprints should be addressed: Depts. of Urology and Genetics, Stanford University, 300 Pasteur Dr. Grant Bldg. S287, Stanford, CA 94305-5118. E-mail: zsun{at}stanford.edu.

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