Document Detail


Expression of oncogenic kinase Bcr-Abl impairs mitotic checkpoint and promotes aberrant divisions and resistance to microtubule-targeting agents.
MedLine Citation:
PMID:  20442314     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Recent findings showed that BRCA1, in addition to its role in DNA damage response, acts as an upstream regulator of genes involved in the mitotic checkpoint regulation, thus protecting against promotion of aberrant divisions and aneuploidy. Moreover, there is also an indication that the BRCA1 protein is downregulated in chronic myeloid leukemia (CML) patients. We have investigated a possible functional relationship between BRCA1 and mitotic checkpoint competence in cells with the same genetic background expressing different levels of Bcr-Abl, an oncogene responsible for CML. Herein, we show that Bcr-Abl strongly downregulates the BRCA1 protein level, which is partially reversed on treatment with imatinib, an inhibitor of Bcr-Abl tyrosine kinase. Bcr-Abl leads to decreased expression of genes involved in the mitotic checkpoint activation--Mad2, Bub1, Bub3, and BubR1, resulting in mitosis perturbances, weakened mitotic checkpoint function, and mitotic slippage after nocodazole treatment. Furthermore, high Bcr-Abl-expressing cells showed also postmitotic checkpoint dysfunctions and inability to effectively arrest in the 4NG1 phase of the cell cycle, which was associated with limited p21 induction. These observations had significant biological consequences, as we found a high level of improper divisions, chromosomal missegregation, and generation of polyploid cells on mitotic checkpoint prolonged activation. Additionally, Bcr-Abl-expressing cells showed resistance to death activated by spindle defects, reversed by imatinib. Our study presents new facts and supports the hypothesis concerning the mutator nature of Bcr-Abl itself. The functional interaction between Bcr-Abl and mitosis dysfunctions, due to compromised mitotic checkpoints, may have important implications for the generation of aneuploidy and CML progression.
Authors:
Kamila Wolanin; Adriana Magalska; Monika Kusio-Kobialka; Paulina Podszywalow-Bartnicka; Susanne Vejda; Sharon L McKenna; Grazyna Mosieniak; Ewa Sikora; Katarzyna Piwocka
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-04
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  9     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-11     Completed Date:  2010-08-20     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1328-38     Citation Subset:  IM    
Affiliation:
Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, Warsaw, Poland.
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MeSH Terms
Descriptor/Qualifier:
Aneuploidy
Animals
Cell Division / genetics*
Cells, Cultured
Disease Progression
Drug Delivery Systems
Drug Resistance, Neoplasm / genetics*
Fusion Proteins, bcr-abl / genetics*,  physiology
Gene Expression Regulation, Leukemic / physiology
Genes, cdc / physiology
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy,  genetics,  pathology
Mice
Microtubules / drug effects
Mitosis / genetics*
Protein-Tyrosine Kinases / genetics*,  physiology
Tubulin Modulators / administration & dosage,  pharmacology,  therapeutic use*
Chemical
Reg. No./Substance:
0/Fusion Proteins, bcr-abl; 0/Tubulin Modulators; EC 2.7.1.-/Bcr-Abl tyrosine kinase; EC 2.7.10.1/Protein-Tyrosine Kinases

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


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