| Resistance to discodermolide, a microtubule-stabilizing agent and senescence inducer, is 4E-BP1-dependent. | |
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MedLine Citation:
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PMID: 21173253 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Discodermolide is a microtubule-stabilizing agent that induces accelerated cell senescence. A discodermolide-resistant cell line, AD32, was generated from the human lung cancer cell line A549. We hypothesize that the major resistance mechanism in these cells is escape from accelerated senescence. AD32 cells have decreased levels of 4E-BP1 mRNA and protein, relative to the parental discodermolide-sensitive A549 cells. Lentiviral-mediated re-expression of wild-type 4E-BP1 in AD32 cells increased the proliferation rate and reverted resistance to discodermolide via restoration of discodermolide-induced accelerated senescence. Consistent with this, cell growth and response to discodermolide was confirmed in vivo using tumor xenograft models. Furthermore, reintroduction of a nonphosphorylatable mutant (Thr-37/46 Ala) of 4E-BP1 was able to partially restore sensitivity and enhance proliferation in AD32 cells, suggesting that these effects are independent of phosphorylation by mTORC1. Microarray profiling of AD32-resistant cells versus sensitive A549 cells, and subsequent unbiased gene ontology analysis, identified molecular pathways and functional groupings of differentially expressed mRNAs implicated in overcoming discodermolide-induced senescence. The most statistically significant classes of differentially expressed genes included p53 signaling, G2/M checkpoint regulation, and genes involved in the role of BRCA1 in the DNA damage response. Consistent with this, p53 protein expression was up-regulated and had increased nuclear localization in AD32 cells relative to parental A549 cells. Furthermore, the stability of p53 was enhanced in AD32 cells. Our studies propose a role for 4E-BP1 as a regulator of discodermolide-induced accelerated senescence. |
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Authors:
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Suzan K Chao; Juan Lin; Jurriaan Brouwer-Visser; Amos B Smith; Susan Band Horwitz; Hayley M McDaid |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-12-20 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 108 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2011-01-05 Completed Date: 2011-02-10 Revised Date: 2011-10-13 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 391-6 Citation Subset: IM |
Affiliation:
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Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. |
| Data Bank Information | |
Bank Name/Acc. No.:
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GEO/GSE25904 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing
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genetics,
metabolism* Alkanes / pharmacology* Animals Antineoplastic Agents / pharmacology* Carbamates / pharmacology* Cell Aging / drug effects* Cell Line, Tumor Cell Proliferation / drug effects Drug Resistance, Neoplasm / physiology* Female Fluorescent Antibody Technique Gene Expression Regulation / drug effects* Genetic Vectors Humans Immunoblotting Immunohistochemistry Lactones / pharmacology* Lentivirus Mice Microarray Analysis Paclitaxel / pharmacology Phosphoproteins / genetics, metabolism* Pyrones / pharmacology* Transduction, Genetic Tubulin Modulators / pharmacology* Tumor Suppressor Protein p53 / metabolism beta-Galactosidase / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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CA077263/CA/NCI NIH HHS; K12CA132783-01A1/CA/NCI NIH HHS; R01 CA077263-12/CA/NCI NIH HHS; T32 GM007491/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Adaptor Proteins, Signal Transducing; 0/Alkanes; 0/Antineoplastic Agents; 0/Carbamates; 0/EIF4EBP1 protein, human; 0/Lactones; 0/Phosphoproteins; 0/Pyrones; 0/Tubulin Modulators; 0/Tumor Suppressor Protein p53; 127943-53-7/discodermolide; 33069-62-4/Paclitaxel; EC 3.2.1.23/beta-Galactosidase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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