| BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. | |
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MedLine Citation:
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PMID: 14559807 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have evaluated the role played by BRCA1 in mediating the phenotypic response to a range of chemotherapeutic agents commonly used in cancer treatment. Here we provide evidence that BRCA1 functions as a differential mediator of chemotherapy-induced apoptosis. Specifically, we demonstrate that BRCA1 mediates sensitivity to apoptosis induced by antimicrotubule agents but conversely induces resistance to DNA-damaging agents. These data are supported by a variety of experimental models including cells with inducible expression of BRCA1, siRNA-mediated inactivation of endogenous BRCA1, and reconstitution of BRCA1-deficient cells with wild-type BRCA1. Most notably we demonstrate that BRCA1 induces a 10-1000-fold increase in resistance to a range of DNA-damaging agents, in particular those that give rise to double-strand breaks such as etoposide or bleomycin. In contrast, BRCA1 induces a >1000-fold increase in sensitivity to the spindle poisons, paclitaxel and vinorelbine. Fluorescence-activated cell sorter analysis demonstrated that BRCA1 mediates G(2)/M arrest in response to both antimicrotubule and DNA-damaging agents. However, poly(ADP-ribose) polymerase and caspase-3 cleavage assays indicate that the differential effect mediated by BRCA1 in response to these agents occurs through the inhibition or induction of apoptosis. Therefore, our data suggest that BRCA1 acts as a differential modulator of apoptosis depending on the nature of the cellular insult. |
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Authors:
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Jennifer E Quinn; Richard D Kennedy; Paul B Mullan; Paula M Gilmore; Michael Carty; Patrick G Johnston; D Paul Harkin |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Cancer research Volume: 63 ISSN: 0008-5472 ISO Abbreviation: Cancer Res. Publication Date: 2003 Oct |
Date Detail:
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Created Date: 2003-10-15 Completed Date: 2003-12-03 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 6221-8 Citation Subset: IM |
Affiliation:
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Department of Oncology, Cancer Research Centre, Queen's University Belfast, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, Northern Ireland, U.K. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents, Phytogenic
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pharmacology* Apoptosis / drug effects*, physiology* BRCA1 Protein / biosynthesis, physiology* Bleomycin / pharmacology Breast Neoplasms / drug therapy*, metabolism, pathology* Cell Line, Tumor Cisplatin / pharmacology DNA Damage Etoposide / pharmacology G2 Phase / drug effects, physiology Humans Microtubules / drug effects, physiology Mitosis / drug effects, physiology Paclitaxel / pharmacology* Vinblastine / analogs & derivatives*, pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents, Phytogenic; 0/BRCA1 Protein; 11056-06-7/Bleomycin; 15663-27-1/Cisplatin; 33069-62-4/Paclitaxel; 33419-42-0/Etoposide; 71486-22-1/vinorelbine; 865-21-4/Vinblastine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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