| Protein kinase C delta stimulates apoptosis by initiating G1 phase cell cycle progression and S phase arrest. | |
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MedLine Citation:
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PMID: 16051606 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Overexpression of protein kinase C delta (PKCdelta) stimulates apoptosis in a wide variety of cell types through a mechanism that is incompletely understood. PKCdelta-deficient cells are impaired in their response to DNA damage-induced apoptosis, suggesting that PKCdelta is required to mount an appropriate apoptotic response under conditions of stress. The mechanism through which it does so remains elusive. In addition to effects on cell survival, PKCdelta elicits pleiotropic effects on cellular proliferation. We now provide the first evidence that the ability of PKCdelta to stimulate apoptosis is intimately linked to its ability to stimulate G(1) phase cell cycle progression. Using an adenoviral-based expression system to express PKCalpha,-delta, and -epsilon in epithelial cells, we demonstrate that a modest increase in PKCdelta activity selectively stimulates quiescent cells to initiate G(1) phase cell cycle progression. Rather than completing the cell cycle, PKCdelta-infected cells arrest in S phase, an event that triggers caspase-dependent apoptotic cell death. Apoptosis was preceded by the activation of cell cycle checkpoints, culminating in the phosphorylation of Chk-1 and p53. Strikingly, blockade of S phase entry using the phosphatidylinositol 3-kinase inhibitor LY294002 prevented checkpoint activation and apoptosis. In contrast, inhibitors of mitogen-activated protein kinase cascades failed to prevent apoptosis. These findings demonstrate that the biological effects of PKCdelta can be extended to include positive regulation of G(1) phase cell cycle progression. Importantly, they reveal the existence of a novel, cell cycle-dependent mechanism through which PKCdelta stimulates cell death. |
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Authors:
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Ademi E Santiago-Walker; Aphrothiti J Fikaris; Gary D Kao; Eric J Brown; Marcelo G Kazanietz; Judy L Meinkoth |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S. Date: 2005-07-28 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 280 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2005 Sep |
Date Detail:
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Created Date: 2005-09-12 Completed Date: 2005-10-20 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 32107-14 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, 19104-6061, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenoviridae
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genetics Animals Apoptosis* Blotting, Western Bromodeoxyuridine / pharmacology Cell Cycle Cell Death Cell Proliferation Chromones / pharmacology DNA / metabolism DNA Damage Enzyme Inhibitors / pharmacology Epithelial Cells / metabolism Flow Cytometry G1 Phase Models, Biological Morpholines / pharmacology Phosphorylation Protein Kinase C / metabolism, physiology* Protein Kinase C-delta Protein Kinases / metabolism Rats Rats, Wistar S Phase Thyroid Gland / cytology Tumor Suppressor Protein p53 / metabolism Up-Regulation |
| Grant Support | |
ID/Acronym/Agency:
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CA-109543/CA/NCI NIH HHS; CA-89202/CA/NCI NIH HHS; CA-92537/CA/NCI NIH HHS; DK-45696/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Chromones; 0/Enzyme Inhibitors; 0/Morpholines; 0/Tumor Suppressor Protein p53; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 59-14-3/Bromodeoxyuridine; 9007-49-2/DNA; EC 2.7.-/Protein Kinases; EC 2.7.1.-/Prkcd protein, rat; EC 2.7.11.1/Checkpoint kinase 1; EC 2.7.11.13/Protein Kinase C; EC 2.7.11.13/Protein Kinase C-delta |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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