9 research outputs found
Diffusion, Mediation, Suppression: India’s Varied Strategy towards the Tamil Insurgency in Sri Lanka
MADD, a Splice Variant of IG20, Is Indispensable for MAPK Activation and Protection against Apoptosis upon Tumor Necrosis Factor-α Treatment*
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-α
(TNFα)-induced activation of NF-κB, 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 TNFα-induced apoptosis in the absence of
cycloheximide. It also resulted in a dramatic loss in TNFα-induced
activation of MAPK without any apparent effect on NF-κB activation. This
observation was substantiated by an accompanying loss in the activation of
p90RSK, a key downstream target of MAPK, whereas the NF-κB-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
TNFα-induced apoptosis. The requirement for MADD was highly specific for
TNFα-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
TNFα-induced apoptosis by specifically activating MAPKs through Grb2 and
Sos1/2 recruitment, and its potential as a novel cancer therapeutic
target