Apoptosis signal-regulating kinase (ASK)-1 mediates apoptosis through activation of JNK1 following engagement of membrane immunoglobulin.

Exp Cell Res

Department of Immunology and Intractable Immunology Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.

Published: December 2009

AI Article Synopsis

  • Engagement of membrane immunoglobulin (mIg) on WEHI-231 mouse B lymphoma cells triggers growth arrest in the G1 phase of the cell cycle, leading to decreased mitochondrial membrane potential and apoptosis.* -
  • The study identifies the ASK1-JNK1 signaling pathway as crucial in mIg-induced apoptosis, primarily by generating reactive oxygen species (ROS) like hydrogen peroxide (H2O2) within the cells.* -
  • Increased expression of active ASK1 enhances apoptosis while dominant-negative ASK1 reduces the effects, indicating a feedback loop between ROS production and ASK1-JNK1 activation that culminates in cell death.*

Article Abstract

Engagement of membrane immunoglobulin (mIg) on WEHI-231 mouse B lymphoma cells results in growth arrest at the G1 phase of the cell cycle, followed by a reduction of mitochondrial membrane potential (DeltaPsim) and apoptosis. WEHI-231 cells resemble immature B cells in terms of the cell surface phenotype and sensitivity to mIg engagement. However, the molecular mechanisms underlying mIg-induced loss of DeltaPsim and apoptosis have not yet been established. In this study, we show that apoptosis signal-regulating kinase 1 (ASK1)-c-Jun N-terminal kinase 1 (JNK1) signaling pathway participates in mIg-induced apoptosis through the generation of reactive oxygen species (ROS). Stimulation of WEHI-231 cells with anti-IgM induces phosphorylation and subsequent activation of ASK1, leading to JNK activation. Anti-IgM stimulation immediately (5 min) induces hydrogen peroxide (H2O2) production with a substantial increase during later time points (36-48 h), accompanied by loss of DeltaPsim and an increase in cells with sub-G1 DNA content. The anti-IgM-induced late-phase H2O2 production, loss of DeltaPsim, and increase in the sub-G1 fraction were all reduced substantially in WEHI-231 cells overexpressing a dominant-negative form of ASK1, compared with control vector alone, but enhanced substantially in cells overexpressing a constitutively active form of ASK1. These mIg-mediated events were also partially abrogated by ROS scavenger N-acetyl-L-cysteine (NAC). Taken together, these results suggest that mIg engagement induces H2O2 production leading to activation of ASK1-JNK1 pathway, creating a feedback amplification loop of ROS-ASK/JNK that leads to loss of DeltaPsim and finally apoptosis.

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http://dx.doi.org/10.1016/j.yexcr.2009.09.007DOI Listing

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