PKCδ mediates Nrf2-dependent protection of neuronal cells from NO-induced apoptosis

Jindan Zhang, Amos C. Hung, Poh Yong Ng, Keiichi Nakayama, Yuanyu Hu, Baojie Li, Alan G. Porter, Saravanakumar Dhakshinamoorthy

Research output: Contribution to journalArticle

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Abstract

A chemical inhibitor library of 84 compounds was screened to investigate the signaling pathway(s) leading to activation of Nrf2 in response to nitric oxide (NO). We identified the protein kinase C delta (PKCδ) inhibitor rottlerin as the only compound that reduced NO-induced ARE-luciferase reporter activity and diminished NO-induced up-regulation of two Nrf2/ARE-regulated proteins - NAD(P)H:quinone oxidoreductase-1 (NQO1) and hemeoxygenase-1 (HO-1) in SH-Sy5y cells. Rottlerin also sensitized neuroblastoma cells and mouse primary cortical neurons to NO-induced apoptosis. Stable over-expression of PKCδ augmented NO-induced, ARE-dependent gene expression of HO-1 in SH-Sy5y cells, which were more protected from NO killing. Conversely, NO-induced ARE-dependent gene expression was reduced in PKCδ-knockdown SH-EP cells, which displayed greater sensitivity to apoptosis. PKCδ-/- cortical neurons exhibited increased NO-induced apoptosis and less HO-1 mRNA and protein induction compared with wild type neurons. Hence, PKCδ is an important positive modulator of NO-induced Nrf2/ARE-dependent signaling that counteracts NO-mediated apoptosis in neuronal cells.

Original languageEnglish
Pages (from-to)750-756
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume386
Issue number4
DOIs
Publication statusPublished - Sep 4 2009

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Protein Kinase C-delta
Cytoprotection
Nitric Oxide
Apoptosis
Heme Oxygenase-1
Neurons
Gene expression
Neuroprotection
Small Molecule Libraries
Gene Expression
Luciferases
Neuroblastoma
NAD
Modulators
Oxidoreductases
Proteins
Up-Regulation
Chemical activation

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

PKCδ mediates Nrf2-dependent protection of neuronal cells from NO-induced apoptosis. / Zhang, Jindan; Hung, Amos C.; Ng, Poh Yong; Nakayama, Keiichi; Hu, Yuanyu; Li, Baojie; Porter, Alan G.; Dhakshinamoorthy, Saravanakumar.

In: Biochemical and Biophysical Research Communications, Vol. 386, No. 4, 04.09.2009, p. 750-756.

Research output: Contribution to journalArticle

Zhang, Jindan ; Hung, Amos C. ; Ng, Poh Yong ; Nakayama, Keiichi ; Hu, Yuanyu ; Li, Baojie ; Porter, Alan G. ; Dhakshinamoorthy, Saravanakumar. / PKCδ mediates Nrf2-dependent protection of neuronal cells from NO-induced apoptosis. In: Biochemical and Biophysical Research Communications. 2009 ; Vol. 386, No. 4. pp. 750-756.
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