TY - JOUR
T1 - Protein kinase C α signaling inhibits cyclin D1 translation in intestinal epithelial cells
AU - Hizli, A. Asli
AU - Black, Adrian R.
AU - Pysz, Marybeth A.
AU - Black, Jennifer D.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006/5/26
Y1 - 2006/5/26
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M601959200
DO - 10.1074/jbc.M601959200
M3 - Article
C2 - 16556598
AN - SCOPUS:33744963882
VL - 281
SP - 14596
EP - 14603
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 21
ER -