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Published online 13 November 2000. doi:10.1083/jcb.151.4.763
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© The Rockefeller University Press, 0021-9525/2000//763 $5.00
The Journal of Cell Biology, Volume 151, Number 4, , 2000 763-778

Original Article

Protein Kinase C Signaling Mediates a Program of Cell Cycle Withdrawal in the Intestinal Epithelium



Mark R. Freya, Jennifer A. Clarka, Olga Leontievaa, Joshua M. Uronisa, Adrian R. Blacka, and Jennifer D. Blacka

a Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Sts., Buffalo, NY 14263. Tel: (716) 845-5766.(716) 845-8857

Members of the protein kinase C (PKC) family of signal transduction molecules have been widely implicated in regulation of cell growth and differentiation, although the underlying molecular mechanisms involved remain poorly defined. Using combined in vitro and in vivo intestinal epithelial model systems, we demonstrate that PKC signaling can trigger a coordinated program of molecular events leading to cell cycle withdrawal into G0. PKC activation in the IEC-18 intestinal crypt cell line resulted in rapid downregulation of D-type cyclins and differential induction of p21waf1/cip1 and p27kip1, thus targeting all of the major G1/S cyclin-dependent kinase complexes. These events were associated with coordinated alterations in expression and phosphorylation of the pocket proteins p107, pRb, and p130 that drive cells to exit the cell cycle into G0 as indicated by concomitant downregulation of the DNA licensing factor cdc6. Manipulation of PKC isozyme levels in IEC-18 cells demonstrated that PKC{alpha} alone can trigger hallmark events of cell cycle withdrawal in intestinal epithelial cells. Notably, analysis of the developmental control of cell cycle regulatory molecules along the crypt–villus axis revealed that PKC{alpha} activation is appropriately positioned within intestinal crypts to trigger this program of cell cycle exit–specific events in situ. Together, these data point to PKC{alpha} as a key regulator of cell cycle withdrawal in the intestinal epithelium.

Key Words: protein kinase C • cell cycle • intestinal mucosa • pocket proteins • cyclin-dependent kinase regulation

© 2000 The Rockefeller University Press

Abbreviations used in this paper: BrdU, 5'-bromo-2'-deoxyuridine; cdk, cyclin-dependent kinase; CKI, cdk inhibitor; DiC8, 1,2-dioctanoyl-sn-glycerol; dPP, 12-deoxyphorbol 13-phenylacetate; dPPA, 12-deoxyphorbol 13-phenylacetate 20-acetate; GFP, green fluorescent protein; PDBu, phorbol 12,13-dibutyrate; PKC, protein kinase C; Res, resiniferatoxin; Thy, thymeleatoxin.


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