Document Detail

cIAP2 represses IKKα/β-mediated activation of MDM2 to prevent p53 degradation.
MedLine Citation:
PMID:  23032264     Owner:  NLM     Status:  MEDLINE    
Cellular inhibitor of apoptosis proteins (cIAP1 and cIAP2) function to prevent apoptosis and are often overexpressed in various cancers. However, mutations in cIAP1/2 can activate the alternative NFκB pathway through IκBα-kinase-α (IKKα) and are associated with hematopoetic malignancies. In the current study, we found that knockdown of cIAP2 in human mammary epithelial cells resulted in activation of MDM2 through increased SUMOylation and profound reduction of the pool of MDM2 not phosphorylated at Ser166. cIAP2 siRNA markedly decreased p53 levels, which were rescued by addition of the MDM2 inhibitor, Nutlin3a. An IAP antagonist, which induces cIAP degradation, transiently increased MDM2 mRNA. Simultaneous transfection of siRNA for cIAP2 and IKKα reduced MDM2 protein, while expression of a kinase-dead IKKβ strongly increased non-Ser166 P-MDM2. Inhibition of either IKKα or -β partially rescued p53 levels, while concomitant IKKα/β inhibition fully rescued p53 after cIAP2 knockdown. Surprisingly, IKKα knockdown alone increased SUMO-MDM2, suggesting that in the absence of activation, IKKα can prevent MDM2 SUMOylation. cIAP2 knockdown disrupted the interaction between the MDM2 SUMO ligase, PIAS1 and IKKα. Partial knockdown of cIAP2 cooperated with (V12) H-ras-transfected mammary epithelial cells to enhance colony formation. In summary, our data identify a novel role for cIAP2 in maintaining wild-type p53 levels by preventing both an NFκB-mediated increase and IKKα/-β-dependent transcriptional and post-translational modifications of MDM2. Thus, mutations or reductions in cIAP2 could contribute to cancer promotion, in part, through downregulation of p53.
Rosanna Lau; Min Ying Niu; M A Christine Pratt
Related Documents :
25009464 - Lrrk2 kinase activity and biology are not uniformly predicted by its autophosphorylatio...
2166904 - 2',3'-dideoxycytidine toxicity in cultured human cem t lymphoblasts: effects of combina...
24563264 - Neuregulin 1-induced akt and erk phosphorylation in patients with fragile x syndrome (f...
21317204 - Androgen receptor levels are upregulated by akt in prostate cancer.
25298094 - Plant-derived flavones as inhibitors of aurora b kinase and their quantitative structur...
9388184 - Specific inhibition of stat3 signal transduction by pias3.
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-03
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  11     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-06     Completed Date:  2013-04-23     Revised Date:  2013-11-05    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4009-19     Citation Subset:  IM    
Breast Cancer Research Lab, University of Ottawa Department of Cellular and Molecular Medicine, Ottawa, ON, Canada.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Cell Line
Down-Regulation / drug effects
Enzyme Inhibitors / pharmacology
I-kappa B Kinase / antagonists & inhibitors,  genetics,  metabolism*
Imidazoles / pharmacology
Inhibitor of Apoptosis Proteins / antagonists & inhibitors,  genetics,  metabolism*
Piperazines / pharmacology
Protein Inhibitors of Activated STAT / metabolism
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors,  genetics,  metabolism*
RNA, Messenger / metabolism
Tumor Suppressor Protein p53 / metabolism*
Grant Support
FRN 79304//Canadian Institutes of Health Research
Reg. No./Substance:
0/BIRC3 protein, human; 0/Enzyme Inhibitors; 0/Imidazoles; 0/Inhibitor of Apoptosis Proteins; 0/Piperazines; 0/Protein Inhibitors of Activated STAT; 0/RNA, Messenger; 0/Tumor Suppressor Protein p53; 0/nutlin 3; EC B Kinase; EC protein, human; EC Proteins c-mdm2

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

Previous Document:  B-Myb promotes S-phase independently of its sequence-specific DNA binding activity and interacts wit...
Next Document:  Historical perspective on advanced drug delivery: How engineering design and mathematical modeling h...