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J. Biol. Chem., Vol. 283, Issue 3, 1293-1307, January 18, 2008

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Smad Signaling Antagonizes STAT5-mediated Gene Transcription and Mammary Epithelial Cell Differentiation^*

From the Hormones and Cancer Research Unit, Department of Medicine, Royal Victoria Hospital, McGill University, Montreal, Quebec H3A 1A1, Canada

Both the transforming growth factor-β (TGFβ)/Smad and the prolactin/JAK/STAT pathway are critical to the proper development, maintenance, and function of the mammary epithelial tissue. Interestingly, opposing physiological effects between these two signaling pathways are prominent in the regulation of mammary gland development. However, the exact nature of the biological network existing between the Smad and STAT signal transduction pathways has remained elusive. We identified a novel regulatory cross-talk mechanism by which TGFβ-induced Smad signaling acts to antagonize prolactin-mediated JAK/STAT signaling and expression of target genes. Furthermore, we found activin, another member of the TGFβ family, to also efficiently block STAT5 signaling and β-casein expression in mammary epithelial cells. Our results indicate that ligand-induced activation of Smad2, -3, and -4 by activin and TGFβ leads to a direct inhibition of STAT5 transactivation and STAT5-mediated transcription of the downstream target genes, β-casein and cyclin D1, thereby blocking vital processes for mammary gland growth and differentiation. Finally, we unveiled the mechanism by which these two signaling cascades antagonize their effects, and we found that activated Smads inhibit STAT5 association with its co-activator CREB-binding protein, thus blocking STAT5 transactivation of its target genes and leading to inhibition of mammary gland differentiation and lactation.

Received for publication, September 6, 2007 , and in revised form, November 16, 2007.

^* This work was supported in part by Grant MOP-53141 from the Canadian Institutes for Health Research (to J. J. L.). 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 Recipient of a McGill University Health Center scholarship.

² Recipient of studentship from the National Cancer Institute of Canada.

³ Research Scientist of the National Cancer Institute of Canada and supported with funds provided by the Canadian Cancer Society.

⁴ To whom correspondence should be addressed: Hormones and Cancer Research Unit, Dept. of Medicine, Royal Victoria Hospital, 687 Pine Ave. West, Montreal, Quebec H3A1A1, Canada. Tel.: 514-934-1934 (Ext. 34846); Fax: 514-982-0893; E-mail: JJ.Lebrun{at}mcgill.ca.

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