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Volume 272, Number 46, Issue of November 14, 1997 pp. 29372-29379
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Activation of the Ste20-like Oxidant Stress Response Kinase-1 during the Initial Stages of Chemical Anoxia-induced Necrotic Cell Death
REQUIREMENT FOR DUAL INPUTS OF OXIDANT STRESS AND INCREASED CYTOSOLIC [Ca²⁺]

(Received for publication, December 9, 1996, and in revised form, August 26, 1997)

Celia M. Pombo ^§ , Toshiya Tsujita ^§ , John M. Kyriakis , Joseph V. Bonventre ^§ and Thomas Force

From the  Cardiac, ^§ Renal, and  Diabetes Units, Massachusetts General Hospital, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02129

Signal transduction mechanisms activated during the early stages of necrotic cell death are poorly characterized. We have recently identified the Sterile 20 (Ste20)-like oxidant stress response kinase-1, SOK-1, which is a member of the Ste20 kinase family. We report that SOK-1 is markedly activated as early as 20 min after chemical anoxia induced by exposure of Madin-Darby canine kidney or LLC-PK₁ renal tubular epithelial cells to 2-deoxyglucose (2-DG) and any one of three inhibitors of the electron transport chain, cyanide (CN), rotenone, or antimycin A. Since oxidant stress activates SOK-1, we postulated that reactive oxygen species (ROS), which are produced by the electron transport chain during chemical anoxia, might be responsible for SOK-1 activation. The time course of CN/2-DG-induced SOK-1 activation and of production of ROS, measured in cells loaded with dichlorofluorescein, were compatible with a role for ROS in SOK-1 activation. Furthermore, preincubation of LLC-PK₁ cells with three unrelated scavengers of ROS, pyrrolidine dithiocarbamate, pyruvate, or nordihydroguaiaretic acid, reduced both cellular oxidant stress and activation of SOK-1 by CN/2-DG. An increase in cytosolic free [Ca²⁺] ([Ca²⁺]_i) was necessary but not sufficient for CN/2-DG-induced activation of SOK-1. Preincubation of cells with BAPTA-AM prevented activation of SOK-1. Incubation of cells with thapsigargin or the calcium ionophore, A23187, had no effect on SOK-1 activity, but preincubation of cells with either of these agents markedly enhanced CN/2-DG-induced activation of SOK-1 (20-fold versus 7-fold). In summary, chemical anoxia activates SOK-1 via an oxidant stress-dependent mechanism that is both critically dependent upon and markedly amplified by an increase in [Ca²⁺]_i. This requirement for dual inputs of oxidant stress and an increase in [Ca²⁺]_i may prevent inappropriate activation of the kinase by milder degrees of oxidant stress, which are insufficient to generate an increase in [Ca²⁺]_i. The activation of SOK-1 may be one of the cell's earliest responses to inducers of necrotic cell death.

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