Document Detail


p53 suppression of arsenite-induced mitotic catastrophe is mediated by p21CIP1/WAF1.
MedLine Citation:
PMID:  16614167     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Arsenic trioxide, an acute promyelocytic leukemia chemotherapeutic, may be an efficacious treatment for other cancers. Understanding the mechanism as well as genetic and molecular characteristics associated with sensitivity to arsenite-induced cell death is key to providing effective chemotherapeutic usage of arsenite. Arsenite sensitivity correlates with deficient p53 pathways in multiple cell lines. The role of p53 in preventing arsenite-induced mitotic arrest-associated apoptosis (MAAA), a form of mitotic catastrophe, was examined in TR9-7 cells, a model cell line with p53 exogenously regulated in a tetracycline-off expression system. Arsenite activated G1 and G2 cell cycle checkpoints independently of p53, but mitotic catastrophe occurred preferentially in p53- cells. Cyclin B/CDC2(CDK1) stabilization and caspase-3 activation persisted in arsenite-treated p53- cells consistent with MAAA/mitotic catastrophe. N-Benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a pan-caspase inhibitor, completely abolished arsenite-induced MAAA/mitotic catastrophe and greatly increased the mitotic index. WEE1 and p21CIP1/WAF1 inhibit cyclin B/CDC2 by CDC2 tyrosine-15 phosphorylation and direct binding, respectively. CDC2-Y15-P was transiently elevated in arsenite-treated p53+ cells but persisted in p53- cells. Arsenite induced p53-S15-P and p21CIP1/WAF1 only in p53+ cells. P21CIP1/WAF1-siRNA-treated p53+ cells were similar to p53- cells in mitotic index and cell cycle protein levels. p53-inducible proteins GADD45alpha and 14-3-3sigma are capable of inhibiting cyclin B/CDC2 but did not play a p53-dependent role in mitotic escape in TR9-7 cells. The data indicate that p53 mediates cyclin B/CDC2 inactivation and mitotic release directly via p21CIP1/WAF1 induction.
Authors:
B Frazier Taylor; Samuel C McNeely; Heather L Miller; Geniece M Lehmann; Michael J McCabe; J Christopher States
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-04-13
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  318     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2006 Jul 
Date Detail:
Created Date:  2006-06-22     Completed Date:  2006-08-14     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  142-51     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Arsenites / pharmacology*
Cell Cycle / drug effects,  physiology
Cell Line, Transformed
Cyclin-Dependent Kinase Inhibitor p21 / physiology*
Genes, p53 / drug effects*,  physiology
Humans
Mitosis / drug effects*,  physiology
Grant Support
ID/Acronym/Agency:
F30 ES013372/ES/NIEHS NIH HHS; F30 ES013372-03/ES/NIEHS NIH HHS; P30 ES001247/ES/NIEHS NIH HHS; P30 ES001247-32/ES/NIEHS NIH HHS; P30 ES01247/ES/NIEHS NIH HHS; R01 ES006460-05/ES/NIEHS NIH HHS; R01 ES011314-04/ES/NIEHS NIH HHS; R01 ES06460/ES/NIEHS NIH HHS; R01 ES11314/ES/NIEHS NIH HHS; T32 ES011564/ES/NIEHS NIH HHS; T32 ES011564-03/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Arsenites; 0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; N5509X556J/arsenite
Comments/Corrections

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