Insulin-like growth factor-I inhibits transcriptional responses of transforming growth factor-β by phosphatidylinositol 3-kinase/ Akt-dependent suppression of the activation of Smad3 but not Smad2

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Abstract

Insulin-like growth factor-I (IGF-I) and transforming growth factor-β (TGF-β) 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-β to regulate expression of several genes in the non-tumorigenic rat prostatic epithelial line, NRP-152. In these cells, IGF-I also inhibits TGF-β-induced transcriptional responses, as shown by several promoter reporter constructs, suggesting that IGF-I intercepts an early step in TGF-β signaling. We show that IGF-I does not down-regulate TGF-β 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-β-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-β-induced transcriptional responses and the activation of Smad3, suggesting that the suppression of TGF-β signaling by IGF-I is mediated through activation of PI3K. Moreover, we show that enforced expression of dominant-negative PI3K (DN-p85α) or phosphatidylinositol 3-phosphate-phosphatase, PTEN, also reverse the suppressive effect of IGF-I on TGF-β-induced 3TP-luciferase reporter activity, whereas constitutively active PI3K (p110αCAAX) completely blocks TGF-β-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-β 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-β transcriptional responses through selective suppression of Smad3 activation via a PI3K/Akt-dependent pathway.

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Song, K., Cornelius, S. C., Reiss, M., & Danielpour, D. (2003). Insulin-like growth factor-I inhibits transcriptional responses of transforming growth factor-β by phosphatidylinositol 3-kinase/ Akt-dependent suppression of the activation of Smad3 but not Smad2. Journal of Biological Chemistry, 278(40), 38342–38351. https://doi.org/10.1074/jbc.M304583200

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