title: Nucleophosmin, a critical Bax cofactor in ischemia-induced cell death.
abstract: We hypothesized that nucleophosmin (NPM), a nucleolar phosphoprotein, is critical for Bax-mediated cell death. To test this hypothesis, Bax activation was induced by metabolic stress. During stress, nucleolar NPM translocated into the cytosol, NPM-Bax complexes formed, and both NPM and Bax accumulated in mitochondria. Expression of a cytosol-restricted NPM mutant (NPM-ΔNLS), but not a nucleus-restricted NPM mutant, increased NPM-Bax complex formation, mitochondrial NPM and Bax accumulation, mitochondrial membrane injury, caspase 3 activation, and ischemia-induced cell death. Coexpression of NPM-ΔNLS with constitutively active Bax mutants caused nearly universal cell death in the absence of metabolic stress, whereas expression of active Bax or NPM-ΔNLS alone did not. A Bax peptide that disrupts NPM-Bax interaction significantly reduced cell death caused by exposure to metabolic inhibitors in vitro and preserved kidney function after ischemia in vivo. Thus, NPM-Bax interaction enhances mitochondrial Bax accumulation, organelle injury, and cell death. NPM-Bax complex formation is a novel target for preventing ischemic tissue injury.
authors: Department of Medicine, Evans Biomedical Research Center, Boston, MA, USA.
authors: Zhiyong
authors: Z
authors: Wang
authors: Jonathan M
authors: JM
authors: Gall
authors: Ramon
authors: R
authors: Bonegio
authors: Andrea
authors: A
authors: Havasi
authors: Katarina
authors: K
authors: Illanes
authors: John H
authors: JH
authors: Schwartz
authors: Steven C
authors: SC
authors: Borkan
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D007511:Ischemia / Q000473:pathology*; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism* / Q000502:physiology; D000090243:Nucleophosmin; D061251:Primary Cell Culture; D011485:Protein Binding; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics; D015427:Reperfusion Injury / Q000378:metabolism; D013312:Stress, Physiological; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494827:Bax protein, mouse; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D000090243:Nucleophosmin