Original Article

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

Correspondence to: Jennifer D. Black, Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Sts., Buffalo, NY 14263. Tel: (716) 845-5766. Fax:(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 p21^waf1/cip1 and p27^kip1, 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 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 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 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

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