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J. Biol. Chem., Vol. 283, Issue 19, 13269-13279, May 9, 2008

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ING2 as a Novel Mediator of Transforming Growth Factor-β-dependent Responses in Epithelial Cells^*

Krishna P. Sarker¹, Hiromi Kataoka¹², Angela Chan¹, Stuart J. Netherton³, Isabelle Pot³, Mai Anh Huynh, Xiaolan Feng, Azad Bonni, Karl Riabowol^¶4, and Shirin Bonni⁵

From the Southern Alberta Cancer Research Institute, Departments of Biochemistry & Molecular Biology and ^¶Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada and the Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115

Members of the ING (inhibitor of growth) family of chromatin modifying proteins (ING1-ING5) have emerged as critical regulators of gene expression and cellular responses, suggesting that the ING proteins may impinge on specific signal transduction pathways and their mediated effects. Here, we demonstrate a role for the protein ING2 in mediating responses by the transforming growth factor (TGF)-β-Smad signaling pathway. We show that ING2 promotes TGF-β-induced transcription. Both gain-of-function and RNA interference-mediated knockdown of endogenous ING2 reveal that ING2 couples TGF-β signals to the induction of transcription and cell cycle arrest. We also find that the Smad-interacting transcriptional modulator SnoN interacts with ING2 and promotes the assembly of a protein complex containing SnoN, ING2, and Smad2. Knockdown of endogenous SnoN blocks the ability of ING2 to promote TGF-β-dependent transcription, and conversely expression of SnoN augments ING2 enhancement of the TGF-β response. Collectively, our data suggest that ING2 collaborates with SnoN to mediate TGF-β-induced Smad-dependent transcription and cellular responses.

Received for publication, October 26, 2007 , and in revised form, February 4, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant NS051255 (to A. B.) and by National Institutes of Health Training Grant GM077226 (to M. A. H.). This work was also supported by grants from the Alberta Cancer Board and the Canadian Institutes of Health Research (to S. B.) and the Harvard Medical School-Merck Sponsored Research Program. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S9.

¹ These authors contributed equally to this work.

² Present address: Nagoya City University Graduate School of Medical Sciences, Dept. of Gastroenterology and Metabolism, 1-Kawasumi, Mizuhocho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.

³ Alberta Heritage Foundation for Medical Research Postdoctoral Fellow.

⁴ Alberta Heritage Foundation for Medical Research Scientist.

⁵ Alberta Heritage Foundation for Medical Research Scholar. To whom correspondence should be addressed: Southern Alberta Cancer Research Inst. and Dept. of Biochemistry & Molecular Biology, Faculty of Medicine, University of Calgary, 3330 Hospital Dr. N.W., Calgary, Alberta T2N 4N1, Canada. Tel.: 403-210-8587; Fax: 403-283-8727; E-mail: sbonni{at}ucalgary.ca.

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