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Papers In Press, published online ahead of print December 11, 2003
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263
Corresponding Author: jennifer.black{at}roswellpark.org
We have previously reported that PKC signaling can mediate a program of cell cycle withdrawal in IEC-18 non-transformed intestinal crypt cells, involving 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 a in mediating these effects. Furthermore, analysis of the signaling events linking PKC/PKC a activation to changes in the cell cycle regulatory machinery implicate the Ras/Raf/MEK/ERK cascade. PKC/PKC a 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 a activation, including cyclin D1 downregulation, p21waf1/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, while 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 a 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 a 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 a and the Ras/Raf/MEK/ERK cascade as key regulators of cell cycle withdrawal in intestinal epithelial cells.
J. Biol. Chem, 10.1074/jbc.M312268200
Submitted on November 10, 2003
Revised on December 10, 2003
Accepted on December 11, 2003
Involvement of the ERK signaling cascade in protein kinase C-mediated cell cycle arrest in intestinal epithelial cells
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