Document Detail


Inducible overexpression of c-Jun in MCF7 cells causes resistance to vinblastine via inhibition of drug-induced apoptosis and senescence at a step subsequent to mitotic arrest.
MedLine Citation:
PMID:  17126817     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
c-Jun is a major component of the AP-1 transcription factor and plays a key role in regulation of diverse biological processes including proliferation and apoptosis. Treatment of a wide variety of cells with the microtubule inhibitor vinblastine leads to a robust increase in c-Jun expression, JNK-mediated c-Jun phosphorylation, and activation of AP-1-dependent transcription. However, the role of c-Jun induction in the response of cells to vinblastine remains obscure. In this study we used MCF7 breast cancer cell lines that express the dominant-negative form of c-Jun, TAM-67, as well as cells that overexpress c-Jun, under the control of an inducible promoter. Vinblastine induced c-Jun protein expression, c-Jun phosphorylation, and AP-1 activation in MCF7 cells, and these parameters were strongly inhibited by inducible TAM-67 expression and strongly enhanced by inducible c-Jun expression. Vinblastine-induced cell death was not affected by TAM-67 expression whereas cells were protected by c-Jun overexpression. Further investigation revealed that apoptotic and senescent cells were observed after vinblastine treatment and that both outcomes were strongly inhibited by c-Jun overexpression. Although c-Jun expression inhibited cell death, it did not affect the ability of vinblastine to induce mitotic arrest. These results indicate that c-Jun expression plays a protective role in the cellular response to vinblastine and operates post-mitotic block to inhibit drug-induced apoptosis and senescence.
Authors:
Lingling Duan; Kristen Sterba; Sergey Kolomeichuk; Heetae Kim; Powel H Brown; Timothy C Chambers
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2006-10-29
Journal Detail:
Title:  Biochemical pharmacology     Volume:  73     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-01-10     Completed Date:  2007-04-23     Revised Date:  2013-06-17    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  481-90     Citation Subset:  IM    
Affiliation:
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Mail Slot 516, 4301 W. Markham Street, Little Rock, AR 72205, United States.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents, Phytogenic / pharmacology
Apoptosis / drug effects*
Cell Aging / drug effects*
Cell Line, Tumor
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Flow Cytometry
G2 Phase / drug effects
Humans
Immunoblotting
Mitosis / drug effects*
Peptide Fragments / metabolism
Phosphorylation / drug effects
Proto-Oncogene Proteins c-jun / metabolism*
Transcription Factor AP-1 / metabolism
Tubulin Modulators / pharmacology
Vinblastine / pharmacology*
Grant Support
ID/Acronym/Agency:
CA-75577/CA/NCI NIH HHS; R01 CA075577/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Peptide Fragments; 0/Proto-Oncogene Proteins c-jun; 0/TAM67 peptide; 0/Transcription Factor AP-1; 0/Tubulin Modulators; 865-21-4/Vinblastine
Comments/Corrections

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