Protein kinase C α signaling inhibits cyclin D1 translation in intestinal epithelial cells

A. Asli Hizli, Adrian R Black, Marybeth A. Pysz, Jennifer D Black

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29 Citations (Scopus)

Abstract

Cyclin D1 is a key regulator of cell proliferation, acting as a mitogen sensor and linking extracellular signaling to the cell cycle machinery. Strict control of cyclin D1 levels is critical for maintenance of tissue homeostasis. We have reported previously that protein kinase C α (PKCα), a negative regulator of cell growth in the intestinal epithelium, promotes rapid down-regulation of cyclin D1 (Frey, M. R., Clark, J. A., Leontieva, O., Uronis, J. M., Black, A. R., and Black, J. D. (2000) J. Cell Biol. 151, 763-778). The current study explores the mechanisms underlying PKCα-induced loss of cyclin D1 protein in non-transformed intestinal epithelial cells. Our findings exclude several mechanisms previously implicated in downregulation of cyclin D1 during cell cycle exit/differentiation, including alterations in cyclin D1 mRNA expression and protein turnover. Instead, we identify PKCα as a novel repressor of cyclin D1 translation, acting at the level of cap-dependent initiation. Inhibition of cyclin D1 translation initiation is mediated by PKCα-induced hypophosphorylation/activation of the translational suppressor 4E-BP1, association of 4E-BP1 with the mRNA cap-binding protein eIF4E, and sequestration of cyclin D1 mRNA in 4E-BP1-associated complexes. Together, these post-transcriptional effects ensure rapid disappearance of the potent mitogenic molecule cyclin D1 during PKCα-induced cell cycle withdrawal in the intestinal epithelium.

Original languageEnglish (US)
Pages (from-to)14596-14603
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number21
DOIs
StatePublished - May 26 2006

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Cyclin D1
Protein Kinase C
Epithelial Cells
Cell Cycle
Cells
Intestinal Mucosa
Tissue homeostasis
Down-Regulation
RNA Cap-Binding Proteins
Messenger RNA
Cell proliferation
Cell growth
Mitogens
Machinery
Proteins
Homeostasis
Chemical activation
Maintenance
Cell Proliferation
Association reactions

ASJC Scopus subject areas

  • Biochemistry

Cite this

Protein kinase C α signaling inhibits cyclin D1 translation in intestinal epithelial cells. / Hizli, A. Asli; Black, Adrian R; Pysz, Marybeth A.; Black, Jennifer D.

In: Journal of Biological Chemistry, Vol. 281, No. 21, 26.05.2006, p. 14596-14603.

Research output: Contribution to journalArticle

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