Document Detail

Critical role of cyclin B1/Cdc2 up-regulation in the induction of mitotic prometaphase arrest in human breast cancer cells treated with 2-methoxyestradiol.
MedLine Citation:
PMID:  22580043     Owner:  NLM     Status:  MEDLINE    
Earlier studies showed that 2-methoxyestradiol (2ME(2)), an endogenous nonpolar metabolite of estradiol-17β, is a strong inducer of G(2)/M cell cycle arrest (based on analysis of cellular DNA content) in human cancer cell lines. The present study sought to investigate the molecular mechanism underlying 2ME(2)-induced cell cycle arrest. We found that 2ME(2) can selectively induce mitotic prometaphase arrest, but not G(2) phase arrest, in cultured MDA-MB-435s and MCF-7 human breast cancer cells. During the induction of prometaphase arrest, there is a time-dependent initial up-regulation of cyclin B1 and Cdc2 proteins, occurring around 12-24h. The strong initial up-regulation of cyclin B1 and Cdc2 matches in timing the 2ME(2)-induced prometaphase arrest. The 2ME(2)-induced prometaphase arrest is abrogated by selective knockdown of cyclin B1 and Cdc2, or by pre-treatment of cells with roscovitine, an inhibitor of cyclin-dependent kinases, or by co-treatment of cells with cycloheximide, a protein synthesis inhibitor that was found to suppress the early up-regulation of cyclin B1 and Cdc2. In addition, we provided evidence showing that MAD2 and JNK1 are important upstream mediators of 2ME(2)-induced up-regulation of cyclin B1 and Cdc2 as well as the subsequent induction of mitotic prometaphase arrest. In conclusion, treatment of human cancer cells with 2ME(2) causes up-regulation of cyclin B1 and Cdc2, which then mediate the induction of mitotic prometaphase arrest.
Hye Joung Choi; Bao Ting Zhu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-05-10
Journal Detail:
Title:  Biochimica et biophysica acta     Volume:  1823     ISSN:  0006-3002     ISO Abbreviation:  Biochim. Biophys. Acta     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-07-03     Completed Date:  2013-02-21     Revised Date:  2014-06-06    
Medline Journal Info:
Nlm Unique ID:  0217513     Medline TA:  Biochim Biophys Acta     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  1306-15     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier B.V. All rights reserved.
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MeSH Terms
Antineoplastic Agents / pharmacology*
Breast Neoplasms
Calcium-Binding Proteins / metabolism
Cell Cycle Proteins / genetics,  metabolism
Cell Line, Tumor
Cell Nucleus Shape / drug effects
Cyclin B / genetics*,  metabolism
Cyclin B1 / genetics*,  metabolism
Estradiol / analogs & derivatives*,  pharmacology
G2 Phase Cell Cycle Checkpoints / drug effects
Gene Knockdown Techniques
Mad2 Proteins
Mitogen-Activated Protein Kinase 8 / metabolism
Prometaphase / drug effects*
RNA Interference
Repressor Proteins / metabolism
Up-Regulation / drug effects*
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents; 0/CCNB1 protein, human; 0/CDC2 protein, human; 0/Calcium-Binding Proteins; 0/Cell Cycle Proteins; 0/Cyclin B; 0/Cyclin B1; 0/MAD2L1 protein, human; 0/Mad2 Proteins; 0/Repressor Proteins; 4TI98Z838E/Estradiol; 6I2QW73SR5/2-methoxyestradiol; EC Protein Kinase 8

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

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