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J. Biol. Chem., Vol. 282, Issue 19, 14213-14225, May 11, 2007

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Protein Kinase C-mediated Down-regulation of Cyclin D1 Involves Activation of the Translational Repressor 4E-BP1 via a Phosphoinositide 3-Kinase/Akt-independent, Protein Phosphatase 2A-dependent Mechanism in Intestinal Epithelial Cells^*

Lingjie Guan, Kyung Song, Marybeth A. Pysz¹, Kathryn J. Curry, A. Asli Hizli, David Danielpour, Adrian R. Black, and Jennifer D. Black²

From the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263 and the Case Comprehensive Cancer Center Research Laboratories and Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106

We reported previously that protein kinase C (PKC), a negative regulator of cell growth in the intestinal epithelium, inhibits cyclin D1 translation by inducing hypophosphorylation/activation of the translational repressor 4E-BP1. The current study explores the molecular mechanisms underlying PKC/PKC-induced activation of 4E-BP1 in IEC-18 nontransformed rat ileal crypt cells. PKC signaling is shown to promote dephosphorylation of Thr⁴⁵ and Ser⁶⁴ on 4E-BP1, residues directly involved in its association with eIF4E. Consistent with the known role of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway in regulation of 4E-BP1, PKC signaling transiently inhibited PI3K activity and Akt phosphorylation in IEC-18 cells. However, PKC/PKC-induced activation of 4E-BP1 was not prevented by constitutively active mutants of PI3K or Akt, indicating that blockade of PI3K/Akt signaling is not the primary effector of 4E-BP1 activation. This idea is supported by the fact that PKC activation did not alter S6 kinase activity in these cells. Further analysis indicated that PKC-mediated 4E-BP1 hypophosphorylation is dependent on the activity of protein phosphatase 2A (PP2A). PKC signaling induced an 2-fold increase in PP2A activity, and phosphatase inhibition blocked the effects of PKC agonists on 4E-BP1 phosphorylation and cyclin D1 expression. H₂O₂ and ceramide, two naturally occurring PKC agonists that promote growth arrest in intestinal cells, activate 4E-BP1 in PKC/PKC-dependent manner, supporting the physiological significance of the findings. Together, our studies indicate that activation of PP2A is an important mechanism underlying PKC/PKC-induced inhibition of cap-dependent translation and growth suppression in intestinal epithelial cells.

Received for publication, November 13, 2006 , and in revised form, March 8, 2007.

^* This work was supported in part by National Institutes of Health Grants DK60632, DK54909, and CA102074 (to D. D.) and CA16056 and by a grant from the Roswell Park Alliance Foundation. 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 Supported by National Institutes of Health Postdoctoral Fellowship CA113048 [GenBank] .

² To whom correspondence should be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Inst., Elm and Carlton St., Buffalo, NY 14263. Tel.: 716-845-5766; Fax: 716-845-8857; E-mail: jennifer.black{at}roswellpark.org.

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