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J. Biol. Chem., Vol. 280, Issue 23, 21858-21866, June 10, 2005

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Smad7 Abrogates Transforming Growth Factor-1-mediated Growth Inhibition in COLO-357 Cells through Functional Inactivation of the Retinoblastoma Protein^*

Nichole Boyer Arnold and Murray Korc

From the Departments of Medicine, and Pharmacology and Toxicology, Dartmouth-Hitchcock Medical Center and Dartmouth Medical School, Hanover, New Hampshire 03755

Smad7 is overexpressed in 50% of human pancreatic cancers. COLO-357 pancreatic cancer cells engineered to overexpress Smad7 are resistant to the actions of transforming growth factor-1 (TGF-1) with respect to growth inhibition and cisplatin-induced apoptosis but not with respect to modulation of gene expression. To delineate the mechanisms underlying these divergent consequences of Smad7 overexpression, we studied the effects of Smad7 on TGF-1-dependent signaling pathways and cell cycle regulating proteins. TGF-1 induced the phosphorylation of MAPK, p38 MAPK, and AKT2 irrespective of the levels of Smad7, and inhibitors of these pathways did not alter TGF-1 actions on cell growth. By contrast, Smad7 overexpression interfered with TGF-1-mediated attenuation of cyclin A and B levels, inhibition of cdc2 dephosphorylation and CDK2 inactivation, up-regulation of p27, and the maintenance of the retinoblastoma protein (RB) in a hypophosphorylated state. Smad7 also suppressed TGF-1-mediated inhibition of E2F activity but did not alter TGF-1-mediated phosphorylation of Smad2, the nuclear translocation of Smad2/3/4, or DNA binding of the Smad2/3/4 complex. Although Smad7 did not associate with the type I TGF- receptor (TRI), SB-431542, an inhibitor of the kinase activity of this receptor, blocked TGF-1-mediated effects on Smad-2 phosphorylation. These findings point toward a novel paradigm whereby Smad7 acts to functionally inactivate RB and de-repress E2F without blocking the activation of TRI and the nuclear translocation of Smad2/3, thereby allowing for TGF-1 to exert effects in a cancer cell that is resistant to TGF-1-mediated growth inhibition.

Received for publication, January 18, 2005 , and in revised form, March 28, 2005.

^* This work was supported by United States Public Health Service Grant CA-75059 (to M. K.). 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.

Recipient of a fellowship award from the George E. Hewitt Foundation for Medical Research.

To whom correspondence should be addressed: Dept. of Medicine, Dartmouth-Hitchcock Medical Center Lebanon, NH 03756. Tel.: 603-650-7936; Fax: 603-650-6122; E-mail: Murray.Korc{at}Dartmouth.edu.

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