Protein kinase C signaling mediates a program of cell cycle withdrawal in the intestinal epithelium

M. R. Frey, J. A. Clark, O. Leontieva, J. M. Uronis, A. R. Black, J. D. Black

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

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 down-regulation 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 PKCα 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 PKCα activation is appropriately positioned within intestinal crypts to trigger this program of cell cycle exit-specific events in situ. Together, these data point to PKCα as a key regulator of cell cycle withdrawal in the intestinal epithelium.

Original languageEnglish (US)
Pages (from-to)763-777
Number of pages15
JournalJournal of Cell Biology
Volume151
Issue number4
DOIs
StatePublished - Nov 13 2000

Keywords

  • Cell cycle
  • Cyclin-dependent kinase regulation
  • Intestinal mucosa
  • Pocket proteins
  • Protein kinase C

ASJC Scopus subject areas

  • Cell Biology

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