title: Physiological roles of ASK1-mediated signal transduction in oxidative stress- and endoplasmic reticulum stress-induced apoptosis: advanced findings from ASK1 knockout mice.
abstract: Apoptosis, a molecularly regulated form of cell death, is essential for the normal functioning and homeostasis of most multicellular organisms, and can be induced by a range of environmental, physical, and chemical stresses. As the cellular decision to live or to die is made by the coordinated action and balancing of many different pro- and antiapoptotic factors, defects in control of this coordination and balance may contribute to a variety of human diseases, including cancer and autoimmune and neurodegenerative conditions. In recent years, multiple factors associated with the execution of apoptosis, such as caspases and Bcl-2 family members, have been discovered and their complicated signaling and molecular interactions have been demonstrated; however, the precise mechanistic basis for intracellular and/or extracellular stress-induced apoptosis remains to be fully characterized. Protein kinases contribute to regulation of life and death decisions made in response to various stress signals, and the actions of pro- and antiapoptotic factors are often affected by modulation of the phosphorylation status of key elements in the execution of apoptosis. Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein (MAP) kinase kinase kinase family, which activates both the MKK4/MKK7-JNK and MKK3/MKK6-p38 MAP kinase pathways and constitutes a pivotal signaling pathway in various types of stress-induced apoptosis. We have recently shown through ASK1 gene ablation in mice that ASK1 plays essential roles in oxidative stress- and endoplasmic reticulum (ER) stress-induced apoptosis. These stresses are closely linked to physiological phenomena in the control of cell fate, and the resultant apoptosis is implicated in the pathophysiology of a broad range of human diseases. This article reviews our new findings on the physiological roles of ASK1-mediated signal transduction in stress responses and the molecular mechanisms by which ASK1 determines cell fate such as survival, differentiation, or apoptosis, with special focus on the regulatory mechanisms of ASK1-mediated apoptosis induced by oxidative stress and ER stress.
authors.affiliation: Laboratory of Cell Signaling, Graduate School, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8549, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuzawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Nishitoh
authors.forename: Kei
authors.initials: K
authors.lastname: Tobiume
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Takeda
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress; D011506:Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D011506:Proteins; D017382:Reactive Oxygen Species; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human; C482859:Map3k5 protein, mouse