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J. Biol. Chem., Vol. 281, Issue 21, 14596-14603, May 26, 2006

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Protein Kinase C Signaling Inhibits Cyclin D1 Translation in Intestinal Epithelial Cells^*

From the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263

Cyclin D1 is a key regulator of cell proliferation, acting as a mitogen sensor and linking extracellular signaling to the cell cycle machinery. Strict control of cyclin D1 levels is critical for maintenance of tissue homeostasis. We have reported previously that protein kinase C (PKC), a negative regulator of cell growth in the intestinal epithelium, promotes rapid down-regulation of cyclin D1 (Frey, M. R., Clark, J. A., Leontieva, O., Uronis, J. M., Black, A. R., and Black, J. D. (2000) J. Cell Biol. 151, 763–778). The current study explores the mechanisms underlying PKC-induced loss of cyclin D1 protein in non-transformed intestinal epithelial cells. Our findings exclude several mechanisms previously implicated in down-regulation of cyclin D1 during cell cycle exit/differentiation, including alterations in cyclin D1 mRNA expression and protein turnover. Instead, we identify PKC as a novel repressor of cyclin D1 translation, acting at the level of cap-dependent initiation. Inhibition of cyclin D1 translation initiation is mediated by PKC-induced hypophosphorylation/activation of the translational suppressor 4E-BP1, association of 4E-BP1 with the mRNA cap-binding protein eIF4E, and sequestration of cyclin D1 mRNA in 4E-BP1-associated complexes. Together, these post-transcriptional effects ensure rapid disappearance of the potent mitogenic molecule cyclin D1 during PKC-induced cell cycle withdrawal in the intestinal epithelium.

Received for publication, March 1, 2006

^* This work was supported in part by National Institutes of Health Grants DK60632, DK54909, and CA16056 and by a grant from the Mae Stone Goode/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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Both authors contributed equally to this work.

² Supported by National Institutes of Health Postdoctoral Fellowship CA113048 [GenBank] .

³ To whom correspondence should be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Inst., Elm and Carlton Sts., Buffalo, NY 14263. Tel.: 716-845-5766; Fax: 716-845-8857; E-mail: jennifer.black{at}roswellpark.org.

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				L. Guan, K. Song, M. A. Pysz, K. J. Curry, A. A. Hizli, D. Danielpour, A. R. Black, and J. D. Black 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 J. Biol. Chem., May 11, 2007; 282(19): 14213 - 14225. [Abstract] [Full Text] [PDF]