| Peripheral-type benzodiazepine receptor (PBR) and PBR drug ligands in fibroblast and fibrosarcoma cell proliferation: role of ERK, c-Jun and ligand-activated PBR-independent pathways. | |
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MedLine Citation:
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PMID: 15130769 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Peripheral-type benzodiazepine receptor (PBR) is a 18-kDa high-affinity drug and cholesterol binding protein, that has been implicated in several physiological processes, such as cholesterol transport and mitochondrial respiration. Specific PBR ligands regulate cell proliferation, although their action is controversial and probably cell-type specific. The aim of the present study was to examine the expression of PBR in cells of mesenchymal origin, i.e. human fibroblasts and fibrosarcoma cells, as well as its role in the regulation of their proliferation. Both mesenchymal cell types express high levels of PBR, localized exclusively in mitochondria. PBR-specific drug ligands, the isoquinoline carboxamide PK 11195 and the benzodiazepine Ro5-4864, at relative high concentrations (10(-4)M), exert a strong inhibitory effect on cell proliferation by arresting the cells at the G0/G1 phase of the cell cycle, while no apoptotic cell death was observed. In normal fibroblasts, this inhibition was correlated with a decrease in the activation of the cell cycle markers ERK and c-Jun. PBR knockdown by RNA inhibition did not affect the proliferation of either cell type and did not influence the inhibitory effect of PK 11195 and Ro5-4864 on cell growth. These data suggest that in fibroblasts and fibrosarcoma cells PBR drug ligands inhibit cell proliferation in a PBR-independent manner. These results are in contrast to data reported on cells of epithelial origin, suggesting that the origin of the cells is crucial in defining the role of PBR in their proliferation, and raise caution in the commonly made assumption that PBR mediates cell functions affected by PBR drug ligands. |
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Authors:
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Dimitris Kletsas; Wenping Li; Zeqiu Han; Vassilios Papadopoulos |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Biochemical pharmacology Volume: 67 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2004 May |
Date Detail:
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Created Date: 2004-05-07 Completed Date: 2004-06-18 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1927-32 Citation Subset: IM |
Affiliation:
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Laboratory of Cell Proliferation and Ageing, Institute of Biology, National Centre for Scientific Research Demokritos, Athens, Greece. dkletsas@bio.demokritos.gr |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology Cell Division / drug effects Fibroblasts / cytology*, drug effects, metabolism Fibrosarcoma / metabolism, pathology* Humans Isoquinolines / pharmacology Ligands Receptors, GABA-A / agonists, metabolism, physiology* Tumor Cells, Cultured |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Isoquinolines; 0/Ligands; 0/Receptors, GABA-A; 85340-56-3/PK 11195 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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