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J. Biol. Chem., Vol. 278, Issue 40, 38342-38351, October 3, 2003

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Insulin-like Growth Factor-I Inhibits Transcriptional Responses of Transforming Growth Factor- by Phosphatidylinositol 3-Kinase/Akt-dependent Suppression of the Activation of Smad3 but Not Smad2^*

Kyung Song , Susan C. Cornelius , Michael Reiss  and David Danielpour  ¶

From the Ireland Cancer Center Research Laboratories and the Department of Pharmacology, Case Western Reserve University/University Hospital of Cleveland, Cleveland, Ohio 44106 and The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901

Insulin-like growth factor-I (IGF-I) and transforming growth factor- (TGF-) have been shown to be oncogenic and tumor suppressive, respectively, on prostate epithelial cells. Here we show that IGF-I inhibits the ability of TGF- to regulate expression of several genes in the non-tumorigenic rat prostatic epithelial line, NRP-152. In these cells, IGF-I also inhibits TGF--induced transcriptional responses, as shown by several promoter reporter constructs, suggesting that IGF-I intercepts an early step in TGF- signaling. We show that IGF-I does not down-regulate TGF- receptor levels, as determined by both receptor cross-linking and Western blot analyses. However, Western blot analysis reveals that IGF-I selectively inhibits the TGF--triggered activation Smad3 but not Smad2, while not altering expression of total Smads 2, 3, or 4. The phosphatidylinositol 3-kinase (PI3K) inhibitor, LY29004 reverses the ability of IGF-I to inhibit TGF--induced transcriptional responses and the activation of Smad3, suggesting that the suppression of TGF- signaling by IGF-I is mediated through activation of PI3K. Moreover, we show that enforced expression of dominant-negative PI3K (DN-p85) or phosphatidylinositol 3-phosphate-phosphatase, PTEN, also reverse the suppressive effect of IGF-I on TGF--induced 3TP-luciferase reporter activity, whereas constitutively active PI3K (p110CAAX) completely blocks TGF--induced 3TP-luciferase reporter activity. Further transfection experiments including expression of constitutively active and dominant-negative Akt and rapamycin treatment suggest that suppression of TGF- signaling/Smad3 activation by IGF-I occurs downstream of Akt and through mammalian target of rapamycin activation. In summary, our data suggest that IGF-I inhibits TGF- transcriptional responses through selective suppression of Smad3 activation via a PI3K/Akt-dependent pathway.

Received for publication, May 2, 2003 , and in revised form, July 21, 2003.

^* This work was supported by NCI, National Institutes of Health Grant 1R01 CA3069-01, Case Western Reserve University Cancer Center Grant P30CA43703, a grant from the Ohio Cancer Research Associates, and intramural funds from the Laboratory of Cell Regulation and Carcinogenesis, NCI, National Institutes of Health. 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.

^¶ To whom correspondence should be addressed: Ireland Cancer Center Research Laboratories, Samuel Gerber Bldg., Ste. 200, Lab 3, 11001 Cedar Ave., Cleveland, OH 44106. Tel.: 216-844-6959; Fax: 216-844-8230; E-mail: dxd49{at}po.cwru.edu.

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