The Mastermind-like 1 (MAML1) Co-activator Regulates Constitutive NF-κB Signaling and Cell Survival

Abstract

Nuclear factor-κB (NF-κB)-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-κB 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-κB signaling via two mechanisms. First, MAML1 co-activates the NF-κB subunit RelA (p65) in NF-κB-dependent transcription. Second, MAML1 causes degradation of the inhibitor of NF-κB (IκBα). Maml1-deficient mouse embryonic fibroblasts showed impaired tumor necrosis factor-α (TNFα)-induced NF-κB responses. Moreover, MAML1 expression level directly influences cellular sensitivity to TNFα-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-κB signaling and regulates cellular survival. Nuclear factor-κB (NF-κB)-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-κB 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-κB signaling via two mechanisms. First, MAML1 co-activates the NF-κB subunit RelA (p65) in NF-κB-dependent transcription. Second, MAML1 causes degradation of the inhibitor of NF-κB (IκBα). Maml1-deficient mouse embryonic fibroblasts showed impaired tumor necrosis factor-α (TNFα)-induced NF-κB responses. Moreover, MAML1 expression level directly influences cellular sensitivity to TNFα-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-κB signaling and regulates cellular survival.