HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/21/14596    most recent M601959200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hizli, A. A. Articles by Black, J. D. Search for Related Content PubMed PubMed Citation Articles by Hizli, A. A. Articles by Black, J. D. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. Tapia, M. Huerta, S. Islas, A. Avila-Flores, E. Lopez-Bayghen, J. Weiske, O. Huber, and L. Gonzalez-Mariscal Zona Occludens-2 Inhibits Cyclin D1 Expression and Cell Proliferation and Exhibits Changes in Localization along the Cell Cycle Mol. Biol. Cell, February 1, 2009; 20(3): 1102 - 1117. [Abstract] [Full Text] [PDF]

				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]