Document Detail


MADD, a splice variant of IG20, is indispensable for MAPK activation and protection against apoptosis upon tumor necrosis factor-alpha treatment.
MedLine Citation:
PMID:  19289468     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We investigated the physiological role of endogenous MAPK-activating death domain-containing protein (MADD), a splice variant of the IG20 gene, that can interact with TNFR1 in tumor necrosis factor-alpha (TNFalpha)-induced activation of NF-kappaB, MAPK, ERK1/2, JNK, and p38. Using exon-specific short hairpin RNAs expressing lentiviruses, we knocked down the expression of all IG20 splice variants or MADD, which is overexpressed in cancer cells. Abrogation of MADD expression rendered cells highly susceptible to TNFalpha-induced apoptosis in the absence of cycloheximide. It also resulted in a dramatic loss in TNFalpha-induced activation of MAPK without any apparent effect on NF-kappaB activation. This observation was substantiated by an accompanying loss in the activation of p90RSK, a key downstream target of MAPK, whereas the NF-kappaB-regulated interleukin 6 levels remained unaffected. Endogenous MADD knockdown, however, did not affect epidermal growth factor-induced MAPK activation thereby demonstrating the specific requirement of MADD for TNF receptor-mediated MAPK activation. Re-expression of short hairpin RNA-resistant MADD in the absence of endogenous IG20 expression rescued the cells from TNFalpha-induced apoptosis. The requirement for MADD was highly specific for TNFalpha-induced activation of MAPK but not the related JNK and p38 kinases. Loss of MADD expression resulted in reduced Grb2 and Sos1/2 recruitment to the TNFR1 complex and decreased Ras and MEKK1/2 activation. These results demonstrate the essential role of MADD in protecting cancer cells from TNFalpha-induced apoptosis by specifically activating MAPKs through Grb2 and Sos1/2 recruitment, and its potential as a novel cancer therapeutic target.
Authors:
Bapi Raju V V S N Kurada; Liang Cheng Li; Nirupama Mulherkar; Mahesh Subramanian; Kanteti V Prasad; Bellur S Prabhakar
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-03-16
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  284     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-05-11     Completed Date:  2009-06-30     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  13533-41     Citation Subset:  IM    
Affiliation:
Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
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MeSH Terms
Descriptor/Qualifier:
Alternative Splicing / genetics
Apoptosis / drug effects*,  genetics
Cycloheximide / pharmacology
Death Domain Receptor Signaling Adaptor Proteins / genetics,  metabolism*
Enzyme Activation / drug effects
Extracellular Signal-Regulated MAP Kinases / genetics,  metabolism*
GRB2 Adaptor Protein / genetics,  metabolism
Gene Silencing
Guanine Nucleotide Exchange Factors / genetics,  metabolism*
HeLa Cells
Humans
Interleukin-6 / pharmacology
NF-kappa B / genetics,  metabolism
Neoplasm Proteins / genetics,  metabolism*
Neoplasms / genetics,  metabolism*,  therapy
Protein Synthesis Inhibitors / pharmacology
Receptors, Tumor Necrosis Factor, Type I / genetics,  metabolism
Ribosomal Protein S6 Kinases, 90-kDa / genetics,  metabolism
SOS1 Protein / genetics,  metabolism
Son of Sevenless Proteins / genetics,  metabolism
Tumor Necrosis Factor-alpha / pharmacology*
Grant Support
ID/Acronym/Agency:
CA107506/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Death Domain Receptor Signaling Adaptor Proteins; 0/GRB2 Adaptor Protein; 0/GRB2 protein, human; 0/Guanine Nucleotide Exchange Factors; 0/IL6 protein, human; 0/Interleukin-6; 0/MADD protein, human; 0/NF-kappa B; 0/Neoplasm Proteins; 0/Protein Synthesis Inhibitors; 0/Receptors, Tumor Necrosis Factor, Type I; 0/SOS1 Protein; 0/SOS2 protein, human; 0/Son of Sevenless Proteins; 0/Tumor Necrosis Factor-alpha; 66-81-9/Cycloheximide; EC 2.7.11.1/Ribosomal Protein S6 Kinases, 90-kDa; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases
Comments/Corrections

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