Role of BI-1 (TEGT)-mediated ERK1/2 activation in mitochondria-mediated apoptosis and splenomegaly in BI-1 transgenic mice

• Published in: Biochimica et biophysica acta 2012-04, Vol.1823 (4), p.876-888
• Main Authors: Kim, Jung-Hyun, Lee, Eung-Ryoung, Jeon, Kilsoo, Choi, Hye Yeon, Lim, Hyejin, Kim, Su-Jeong, Chae, Han-Jung, Park, Seung Hwa, Kim, SangUk, Seo, Young Rok, Kim, Jin-Hoi, Cho, Ssang-Goo
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Apoptosis - drug effects; Autoimmune response; Bax inhibitor-1; BI-1 family protein; Computational Biology; Cytoprotection - drug effects; Down-Regulation - drug effects; Enzyme Activation - drug effects; ERK1/2; Etoposide - pharmacology; Fibroblasts - drug effects; Fibroblasts - enzymology; Fibroblasts - pathology; HEK293 Cells; Humans; MAP Kinase Signaling System - drug effects; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Mice; Mice, Transgenic; Mitochondria - drug effects; Mitochondria - enzymology; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Molecular Sequence Data; Reactive Oxygen Species - metabolism; Splenomegaly; Splenomegaly - enzymology; Splenomegaly - pathology; Stress, Physiological - drug effects
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2012.01.016

Bax Inhibitor-1 (BI-1) is an evolutionally conserved apoptotic suppressor and belongs to the BI-1 family of proteins, which contain BI-1-like transmembrane domains. As their cellular functions and regulatory mechanisms remain incompletely understood, we compared their anti-apoptotic properties. Forced expression of BI-1 resulted in the most effective suppression of stress-induced apoptosis, compared with other family members, together with significant extracellular signal-regulated kinase (ERK)1/2 activation. BI-1-mediated ERK1/2 activation led to the suppression of mitochondria-mediated reactive oxygen species (ROS) production. Involvement of the ERK signaling pathway in BI-1-induced anti-apoptotic effects was confirmed by knockdown studies with ERK- or BI-1-specific siRNA. Moreover, we produced transgenic (TG) mice overexpressing BI-1, and the relationship between ERK1/2 activation and the suppression of ROS production or apoptosis was confirmed in mouse embryonic fibroblast (MEF) cells derived from these mice. Interestingly, we found that BI-1 TG mice showed splenomegaly and abnormal megakaryopoiesis. Taken together, our results suggest that BI-1-induced ERK1/2 activation plays an important role in the modulation of intracellular ROS generation and apoptotic cell death and may also affect autoimmune response. ► BI-1 shows most effective suppression of stress-induced apoptosis, compared with other BI-1 family members. ► BI-1 overexpression leads to the induction of ERK 1/2 phosphorylation in a sustained pattern. ► ERK activation is important for the anti-apoptotic function of BI-1. ► Transgenic mice overexpressing BI-1 shows splenomegaly and extramedullary megakaryopoiesis.