Document Detail


Myosin VI is differentially regulated by DNA damage in p53- and cell type-dependent manners.
MedLine Citation:
PMID:  20576604     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Myosin VI is an unconventional motor protein and functions in a variety of intracellular processes such as cell migration, vesicular trafficking, and homeostasis of the Golgi complex. Previously, we found that myosin VI is up-regulated in RKO, LS174T, and H1299 cells by DNA damage in a p53-dependent manner and mediates the pro-survival function of p53. Here, we showed that the levels of myosin VI protein were markedly inhibited in MCF7 and LNCaP cells by topoisomerase I-II inhibitors. However, the levels of myosin VI transcript were decreased only by topoisomerase I inhibitors. We also found that the levels of myosin VI protein were markedly inhibited in MCF7 cells by wild-type p53 but not tumor-derived mutant p53. Surprisingly, we found that the level of myosin VI transcript was slightly increased instead of decreased in MCF7 cells by p53, suggesting that a mechanism other than transcriptional repression is involved. Additionally, we found that on the myosin VI promoter, the level of acetylated histone H3 was markedly decreased, whereas that of p53 and acetylated histone H4 was slightly increased in MCF7 cells upon treatment with topoisomerase I-II inhibitors. Finally, we showed that overexpression of myosin VI enhances, whereas knockdown of myosin VI decreases, DNA damage-induced stabilization of p53, and consequently, knockdown of myosin VI de-sensitizes MCF7 cells to DNA damage-induced apoptosis. Taken together, as a mediator of the p53 pro-survival pathway and a marker of malignancy in some tumors, differential regulation of myosin VI in various tumor cells by topoisomerase inhibitors dictates whether knockdown of myosin VI inhibits, rather than enhances, the susceptibility of tumor cells to some therapeutic agents, which might be explored for designing a proper therapeutic strategy.
Authors:
Seong Jun Cho; Xinbin Chen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-06-23
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-23     Completed Date:  2010-09-17     Revised Date:  2011-08-30    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  27159-66     Citation Subset:  IM    
Affiliation:
Department of Surgical and Radiological Sciences, Comparative Cancer Center, University of California, Davis, California 95616, USA.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis*
Cell Line, Tumor
Cell Survival / drug effects,  genetics
DNA Damage*
DNA Topoisomerases, Type I / metabolism
DNA Topoisomerases, Type II / metabolism
Enzyme Inhibitors / pharmacology
Histones / genetics,  metabolism
Humans
Mutation
Myosin Heavy Chains / genetics,  metabolism*
Neoplasms / drug therapy,  genetics,  metabolism
RNA, Messenger / genetics,  metabolism
Topoisomerase I Inhibitors
Topoisomerase II Inhibitors
Transcription, Genetic*
Tumor Suppressor Protein p53 / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
CA076069/CA/NCI NIH HHS; CA121137/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Histones; 0/Myosin Heavy Chains; 0/RNA, Messenger; 0/TP53 protein, human; 0/Topoisomerase I Inhibitors; 0/Topoisomerase II Inhibitors; 0/Tumor Suppressor Protein p53; 0/myosin VI; EC 5.99.1.2/DNA Topoisomerases, Type I; EC 5.99.1.3/DNA Topoisomerases, Type II
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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