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

doi:10.1083/jcb.151.4.763

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. Frey^a, Jennifer A. Clark^a, Olga Leontieva^a, Joshua M. Uronis^a, Adrian R. Black^a, and Jennifer D. Black^a

^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 transductionmolecules have been widely implicated in regulation of cellgrowth and differentiation, although the underlying molecularmechanisms involved remain poorly defined. Using combined invitro and in vivo intestinal epithelial model systems, we demonstratethat PKC signaling can trigger a coordinated program of molecularevents leading to cell cycle withdrawal into G₀. PKC activationin the IEC-18 intestinal crypt cell line resulted in rapid downregulationof D-type cyclins and differential induction of p21^waf1/cip1and p27^kip1, thus targeting all of the major G₁/S cyclin-dependentkinase complexes. These events were associated with coordinatedalterations in expression and phosphorylation of the pocketproteins p107, pRb, and p130 that drive cells to exit the cellcycle into G₀ as indicated by concomitant downregulation ofthe DNA licensing factor cdc6. Manipulation of PKC isozyme levelsin IEC-18 cells demonstrated that PKC ${alpha}$ alone can trigger hallmarkevents of cell cycle withdrawal in intestinal epithelial cells.Notably, analysis of the developmental control of cell cycleregulatory molecules along the crypt–villus axis revealedthat PKC ${alpha}$ activation is appropriately positioned within intestinalcrypts to trigger this program of cell cycle exit–specificevents in situ. Together, these data point to PKC ${alpha}$ as a key regulatorof cell cycle withdrawal in the intestinal epithelium.

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

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-deoxyphorbol13-phenylacetate 20-acetate; GFP, green fluorescent protein;PDBu, phorbol 12,13-dibutyrate; PKC, protein kinase C; Res,resiniferatoxin; Thy, thymeleatoxin.

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