The mastermind-like 1 (MAML1) co-activator regulates constitutive NF-kappaB signaling and cell survival.
Nuclear factor-kappaB (NF-kappaB)-based signaling regulates diverse biological processes, and its deregulation is associated with various disorders including autoimmune diseases and cancer. Identification of novel factors that modulate NF-kappaB function is therefore of significant importance. The Mastermind-like 1 (MAML1) transcriptional co-activator regulates transcriptional activity in the Notch pathway and is emerging as a co-activator of other pathways. In this study, we found that MAML1 regulates NF-kappaB signaling via two mechanisms. First, MAML1 co-activates the NF-kappaB subunit RelA (p65) in NF-kappaB-dependent transcription. Second, MAML1 causes degradation of the inhibitor of NF-kappaB (IkappaBalpha). Maml1-deficient mouse embryonic fibroblasts showed impaired tumor necrosis factor-alpha (TNFalpha)-induced NF-kappaB responses. Moreover, MAML1 expression level directly influences cellular sensitivity to TNFalpha-induced cytotoxicity. In vivo, mice deficient in the Maml1 gene exhibited spontaneous cell death in the liver, with a large increase in the number of apoptotic hepatic cells. These findings indicate that MAML1 is a novel modulator for NF-kappaB signaling and regulates cellular survival.
Jin
Baofeng
B
Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, Florida 32610, USA.
Shen
Huangxuan
H
Lin
Shuibin
S
Li
Jian-Liang
JL
Chen
Zirong
Z
Griffin
James D
JD
Wu
Lizi
L
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020672:I-kappa B Proteins / Q000378:metabolism*; D047468:Immunoprecipitation; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D020672:I-kappa B Proteins; C486455:Maml1 protein, mouse; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha