Document Detail


hBub1 negatively regulates p53 mediated early cell death upon mitotic checkpoint activation.
MedLine Citation:
PMID:  19252416     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Our previous studies showed that the depletion of the outer kinetochore protein hBub1 upon activation of spindle assembly checkpoint (SAC) primarily triggers early cell death mediated by p53 rather than aneuploidy. Here, we report that phosphorylation of p53 at Ser37 is critical for proapoptotic activity upon SAC activation. Furthermore, we show that p53 physically interacts with hBub1 at kinetochores in response to mitotic spindle damage suggesting a direct role for hBub1 in the suppression of p53 mediated cell death. This observation is further substantiated by the inhibition of p53 mediated transactivation of the proapoptotic target genes, PUMA and BAX, by hBub1 in SAC activated cells. In summary, our data from these and our previous studies strongly suggest that in response to SAC activation, hBub1 acts as a negative regulator of p53 mediated early cell death in a novel checkpoint pathway. On the translational medicine front, it is tempting to speculate that by disabling hBub1 in p53 proficient cancer cells, apoptosis may be induced as a therapeutic approach to eradicate the tumor cells.
Authors:
Fangming Gao; Jose F Ponte; Mary Levy; Panagiotis Papageorgis; Nathaniel M Cook; Sait Ozturk; Arthur W Lambert; Arunthathi Thiagalingam; Hamid M Abdolmaleky; Beth A Sullivan; Sam Thiagalingam
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-04-22
Journal Detail:
Title:  Cancer biology & therapy     Volume:  8     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-05-06     Completed Date:  2009-08-27     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  548-56     Citation Subset:  IM    
Affiliation:
Department of Medicine, Genetics Program and Cancer Research Center, Boston University School of Medicine, Boston, MA, USA.
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MeSH Terms
Descriptor/Qualifier:
Cell Cycle / physiology
Cell Death / genetics
Cell Line, Tumor
Fluorescent Antibody Technique
HCT116 Cells
Humans
Immunoblotting
Immunoprecipitation
Mitotic Spindle Apparatus / genetics,  metabolism*
Nocodazole / pharmacology
Phosphorylation
Protein Kinases / genetics,  metabolism
Protein-Serine-Threonine Kinases / genetics,  metabolism*
Tumor Suppressor Protein p53 / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
CA101773/CA/NCI NIH HHS; T32HL07035/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 31430-18-9/Nocodazole; EC 2.7.-/Protein Kinases; EC 2.7.11.1/Bub1 spindle checkpoint protein; EC 2.7.11.1/Protein-Serine-Threonine Kinases

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


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