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C-terminal mechano-growth factor induces heme oxygenase-1-mediated neuroprotection of SH-SY5Y cells via the protein kinase Cϵ/Nrf2 pathway

Authors

  • Arnulfo Quesada,

    Corresponding author
    1. Department of Neurobiology, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California
    2. Research Service, VA Greater Los Angeles Healthcare System, Los Angeles California
    • VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd. (151), Los Angeles, CA 90073
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    • Arnulfo Quesada and Adrian Handforth contributed equally to this work.

  • Julie Ogi,

    1. Research Service, VA Greater Los Angeles Healthcare System, Los Angeles California
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  • James Schultz,

    1. Research Service, VA Greater Los Angeles Healthcare System, Los Angeles California
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  • Adrian Handforth

    1. Neurology Service, VA Greater Los Angeles Healthcare System, Los Angeles California
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    • Arnulfo Quesada and Adrian Handforth contributed equally to this work.

Errata

This article is corrected by:

  1. Errata: C-terminal mechano-growth factor induces heme oxygenase-1-mediated neuroprotection of SH-SY5Y cells via the protein kinase Ce/Nrf2 pathway Volume 89, Issue 7, 1142, Article first published online: 12 April 2011

  • This article is a US Government work and, as such, is in the public domain in the United States of America.

Abstract

Recently, a variant of insulin-like growth factor-1, mechano-growth factor (MGF), has been discovered whose 24-amino-acid carboxy end is protective in models of stroke, nerve injury, and amyotrophic lateral sclerosis, suggesting broad-spectrum neuroprotective properties. Moreover, we recently demonstrated in vitro and in vivo that a modified protease-resistant 24-amino-acid MGF derivative (MGF24) protects dopaminergic neurons from oxidative stress-induced apoptosis via induction of the stress response protein heme oxygenase-1. However, the underlying mechanism by which MGF24 up-regulates heme oxygenase-1 expression is unknown. In this study, we demonstrate that MGF24-induced heme oxygenase-1 up-regulation is dependent on activation of protein kinase Cϵ and NF-E2-related factor-2 (Nrf2). MGF24 induces nuclear translocation of Nrf2, and siRNA knockdown of Nrf2 or of heme oxygenase-1 prevents MGF24-induced heme oxygenase-1 up-regulation and neuroprotection of SH-SY5Y cells against 6-hydroxydopamine-induced cell death. Pharmacological inhibition of ERK, p38 MAPK, PI3K/Akt, or PKC signaling revealed that only PKC inhibition by GF109203X prevents MGF24's ability to protect against 6-hydroxydopamine-induced cell death. GF109203X also prevented MGF24-induced Nrf2 nuclear translocation and heme oxygenase-1 up-regulation. siRNA knockdown of protein kinase Cϵ blocks MGF24-induced Nfr2 nuclear translocation, heme oxygenase-1 expression, and neuroprotection. Taken together, these results demonstrate that PKC activity is needed for MGF24's activation of Nrf2, which in turn increases heme oxygenase-1 expression, a critical event in mediating MGF24's neuroprotection against 6-hydroxydopamine-induced apoptosis. Published 2011 Wiley-Liss, Inc.

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