ArticleThe Journal of biological chemistry2009
MADD, a splice variant of IG20, is indispensable for MAPK activation and protection against apoptosis upon tumor necrosis factor-alpha treatment.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 56 citations in OpenAlex.
- CRISPR/Cas9-mediated deletion of MADD induces cell cycle arrest and apoptosis in anaplastic thyroid cancer cells.Scientific reports · 2025Article
- A splice site variant in MADD affects hormone expression in pancreatic β cells and pituitary gonadotropes.JCI insight · 2024Article
- Article
- Salivary proteins offer insights into keratinocyte death during aphthous stomatitis. A case-crossover study.BMC oral health · 2023Article
- A single-nucleus transcriptome-wide association study implicates novel genes in depression pathogenesis.medRxiv : the preprint server for health sciences · 2023Article
- Grb2 interacts with necrosome components and is involved in rasfonin-induced necroptosis.Cell death discovery · 2022Article
- Role of Non-Coding RNA in Neurological Complications Associated With Enterovirus 71.Frontiers in cellular and infection microbiology · 2022Review
- Modulatory role of miRNAs in thyroid and breast cancer progression and insights into their therapeutic manipulation.Current research in pharmacology and drug discovery · 2022Review
- Childhood Obesity-Related Mechanisms: MicroRNome and Transcriptome Changes in a Nested Case-Control Study.Biomedicines · 2021Article
- Review
- A role for alternative splicing in circadian control of exocytosis and glucose homeostasis.Genes & development · 2020Article
- Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder.Brain : a journal of neurology · 2020Article
- Nucleotide exchange factor Rab3GEP requires DENN and non-DENN elements for activation and targeting of Rab27a.Journal of cell science · 2019Article
- Loss of MADD expression inhibits cellular growth and metastasis in anaplastic thyroid cancer.Cell death & disease · 2019Article
- MUDENG Expression Profiling in Cohorts and Brain Tumor Biospecimens to Evaluate Its Role in Cancer.Frontiers in genetics · 2019Article
- Article
- TDP-43 affects splicing profiles and isoform production of genes involved in the apoptotic and mitotic cellular pathways.Nucleic acids research · 2015Article
- Data-derived modeling characterizes plasticity of MAPK signaling in melanoma.PLoS computational biology · 2014Article
- Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic β cells.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.