Document Detail


Arsenic Trioxide Induces Abnormal Mitotic Spindles through a PIP4KIIγ/Rho Pathway.
MedLine Citation:
PMID:  22496355     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Arsenite-induced spindle abnormalities result in mitotic cell apoptosis in several cancer cell lines, but how arsenite induces these effects is not known. Evidence to date has revealed that arsenite activates Rho GTPases. Because Rho GTPases regulate spindle orientation, chromosome congression, and cytokinesis, we therefore examined the involvement of Rho GTPases and their modulators in arsenite-induced mitotic abnormalities. We demonstrated that arsenic trioxide (ATO) disrupted the positioning of bipolar mitotic spindles and induced centrosome and spindle abnormalities. ATO increased the level of the active GTP-bound form of Rho. Inhibition of Rho-associated protein kinases (ROCKs) by Y-27632 ameliorated ATO-induced spindle defects, mitotic arrest, and cell death. These results indicate that ATO may induce spindle abnormalities and mitotic cell death through a Rho/ROCK pathway. In addition, screening of a human kinase and phosphatase shRNA library to select genes that mediate ATO induction of spindle abnormalities resulted in the identification of phosphatidylinositol-5-phosphate 4-kinase type-2 gamma (PIP4KIIγ), a phosphatidylinositol 4,5-biphosphate (PIP2) synthesis enzyme that belongs to the phosphatidylinositol phosphate kinase (PIPK) family. Sequestration of PIP2 by ectopic overexpression of the pleckstrin homology domain of phospholipase C-δ1 protected cells from ATO-induced cell death. Furthermore, depletion of PIP4KIIγ, but not other isoforms of the PIPK family, not only reduced Rho GTPase activation in ATO-treated cells but also alleviated ATO-induced spindle defects, mitotic arrest, and mitotic cell apoptosis. Thus, our results imply that ATO induces abnormalities in mitotic spindles through a PIP4KIIγ/Rho pathway, leading to apoptosis of mitotic cells.
Authors:
Ling-Huei Yih; Yi-Chen Wu; Nai-Chi Hsu; Hsiao-Hui Kuo
Related Documents :
18618675 - 17beta-estradiol attenuates hyperoxia-induced apoptosis in mouse c8-d1a cell line.
22886415 - Cardiac mitochondrial matrix and respiratory complex protein phosphorylation.
22496355 - Arsenic trioxide induces abnormal mitotic spindles through a pip4kiiγ/rho pathway.
17283155 - Bcl-2 protects endothelial cells against gamma-radiation via a raf-mek-erk-survivin sig...
9735365 - Role of nudel protease activation in triggering dorsoventral polarization of the drosop...
14974085 - Noonan syndrome-associated shp2/ptpn11 mutants cause egf-dependent prolonged gab1 bindi...
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-10
Journal Detail:
Title:  Toxicological sciences : an official journal of the Society of Toxicology     Volume:  -     ISSN:  1096-0929     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-4-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9805461     Medline TA:  Toxicol Sci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, Republic of China.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:

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


Previous Document:  Tuberculosis Diagnostics and Biomarkers: Needs, Challenges, Recent Advances, and Opportunities.
Next Document:  Inhibition of the Heat Shock Response by PI103 Enhances the Cytotoxicity of Arsenic Trioxide.