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J. Biol. Chem., Vol. 279, Issue 10, 9233-9247, March 5, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/10/9233    most recent M312268200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clark, J. A. Articles by Black, J. D. Search for Related Content PubMed PubMed Citation Articles by Clark, J. A. Articles by Black, J. D. Social Bookmarking                      What's this?

Involvement of the ERK Signaling Cascade in Protein Kinase C-mediated Cell Cycle Arrest in Intestinal Epithelial Cells^*

Jennifer A. Clark, Adrian R. Black, Olga V. Leontieva, Mark R. Frey, Marybeth A. Pysz, Laura Kunneva, Anna Woloszynska-Read, Durga Roy, and Jennifer D. Black

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

We have reported previously that protein kinase C (PKC) signaling can mediate a program of cell cycle withdrawal in IEC-18 nontransformed intestinal crypt cells, involving rapid disappearance of cyclin D1, increased expression of Cip/Kip cyclin-dependent kinase inhibitors, and activation of the growth suppressor function of pocket proteins (Frey, M. R., Clark, J. A., Leontieva, O., Uronis, J. M., Black, A. R., and Black, J. D. (2000) J. Cell Biol. 151, 763–777). In the current study, we present evidence to support a requisite role for PKC in mediating these effects. Furthermore, analysis of the signaling events linking PKC/PKC activation to changes in the cell cycle regulatory machinery implicate the Ras/Raf/MEK/ERK cascade. PKC/PKC activity promoted GTP loading of Ras, activation of Raf-1, and phosphorylation/activation of ERK. ERK activation was found to be required for critical downstream effects of PKC/PKC activation, including cyclin D1 down-regulation, p21^Waf1/Cip1 induction, and cell cycle arrest. PKC-induced ERK activation was strong and sustained relative to that produced by proliferative signals, and the growth inhibitory effects of PKC agonists were dominant over proliferative events when these opposing stimuli were administered simultaneously. PKC signaling promoted cytoplasmic and nuclear accumulation of ERK activity, whereas growth factor-induced phospho-ERK was localized only in the cytoplasm. Comparison of the effects of PKC agonists that differ in their ability to sustain PKC activation and growth arrest in IEC-18 cells, together with the use of selective kinase inhibitors, indicated that the length of PKC-mediated cell cycle exit is dictated by the magnitude/duration of input signal (i.e. PKC activity) and of activation of the ERK cascade. The extent/duration of phospho-ERK nuclear localization may also be important determinants of the duration of PKC agonist-induced growth arrest in this system. Taken together, the data point to PKC and the Ras/Raf/MEK/ERK cascade as key regulators of cell cycle withdrawal in intestinal epithelial cells.

Received for publication, November 10, 2003 , and in revised form, December 10, 2003.

^* This work was supported by National Institutes of Health Grants DK54909, DK60632, and CA16056, by a grant from the Crohn's and Colitis Foundation of America, and by grants from the Roswell Park Alliance Foundation and the Mae Stone Goode 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.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Institute, 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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