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J. Biol. Chem., Vol. 280, Issue 13, 13037-13046, April 1, 2005

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SnoN Is a Cell Type-specific Mediator of Transforming Growth Factor- Responses^*

Krishna P. Sarker, Sylvia M. Wilson, and Shirin Bonni, An Alberta Heritage Foundation for Medical Research Scholar and Alberta Cancer Board New Investigator

From the Cancer Biology Research Group and Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada

The transforming growth factor- (TGF-) family of secreted proteins have pleiotropic functions that are critical to normal development and homeostasis. However, the intracellular mechanisms by which the TGF- proteins elicit cellular responses remain incompletely understood. The Smad proteins provide a major means for the propagation of the TGF- signal from the cell surface to the nucleus, where the Smad proteins regulate gene expression leading to TGF--dependent cellular responses including the inhibition of cell proliferation. Recent studies have suggested that a nuclear Smad-interacting protein termed SnoN, when overexpressed in cells, suppresses TGF--induced Smad signaling and TGF- inhibition of cell proliferation. However, the physiologic function of endogenous SnoN in TGF--mediated biological responses remained to be elucidated. Here, we determined the effect of genetic knock-down of SnoN by RNA interference on TGF- responses in mammalian cells. Unexpectedly, we found that SnoN knock-down specifically inhibited TGF--induced transcription in the lung epithelial cell line Mv1Lu but not in HeLa or HaCaT cells. SnoN knock-down was also found to block TGF--dependent cell cycle arrest in Mv1Lu cells. Collectively, these data indicate that rather than suppressing TGF--induced responses, endogenous SnoN acts as a positive mediator of TGF--induced transcription and cell cycle arrest in lung epithelial cells. Our study also shows that SnoN couples the TGF- signal to gene expression in a cell-specific manner.

Received for publication, August 16, 2004 , and in revised form, December 15, 2004.

^* This work is supported by grants from the Canadian Institutes for Health Research, Alberta Heritage Foundation for Medical Research, and Alberta Cancer Board. 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.

An Alberta Cancer Board Postdoctoral Fellow.

To whom correspondence should be addressed: Cancer Biology Research Group and Dept. of Biochemistry and 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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