EGFR-independent activation of p38 MAPK and EGFR-dependent activation of ERK1/2 are required for ROS-induced renal cell death

Jing Dong, Sampath Ramachandiran, Kulbhushan Tikoo, Zhe Jia, Serrine Lau, Terrence Monks

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

2,3,5-Tris-(glutathion-S-yl)hydroquinone (TGHQ), a reactive metabolite of the nephrotoxicant hydroquinone, induces the ROS-dependent activation of MAPKs, followed by histone H3 phosphorylation and oncotic cell death in renal proximal tubule epithelial cells (LLC-PK1). Cell death and histone H3 phosphorylation are attenuated by pharmacological inhibition of p38 MAPK or ERK1/2 pathways. Because TGHQ, but not epidermal growth factor (EGF), induces histone H3 phosphorylation and cell death in LLC-PK1 cells, we hypothesized that there are differences in the mechanisms by which TGHQ and EGF induce activation of the EGF receptor (EGFR). We therefore compared the relative ability of TGHQ, H2O2, and EGF to activate EGFR and MAPKs and found that p38 MAPK activation is EGFR independent, whereas ERK1/2 activation occurs mainly through EGFR activation. TGHQ, H2O 2, and EGF induce different EGFR tyrosine phosphorylation profiles that likely influence the subsequent differential kinetics of MAPK activation. We next transfected LLC-PK1 cells with a dominant negative p38 MAPK-expressing plasmid (pcDNA3-DNp38). TGHQ failed to induce phosphorylation of p38 MAPK and its substrate, MK-2, in pcDNA3-DNp38-transfected cells, indicating loss of function of p38 MAPK. In untransfected, pcDNA3 or pcDNA3-p38 (native)-transfected LLC-PK1 cells, Hsp27 was intensively phosphorylated after TGHQ treatment, whereas in pcDNA3-DNp38-transfected cells, TGHQ failed to induce Hsp27 phosphorylation. Thus EGFR-independent p38 MAPK and EGFR-dependent ERK1/2 activation by TGHQ lead to the activation of two downstream signaling factors, i.e., histone H3 and Hsp27 phosphorylation, which have in common the potential ability to remodel chromatin.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume287
Issue number5 56-5
DOIs
StatePublished - Nov 2004

Fingerprint

p38 Mitogen-Activated Protein Kinases
Epidermal Growth Factor Receptor
Cell Death
Phosphorylation
Kidney
LLC-PK1 Cells
Epidermal Growth Factor
Histones
Proximal Kidney Tubule
MAP Kinase Signaling System
Chromatin
Tyrosine
Plasmids
Epithelial Cells
Pharmacology

Keywords

  • Epidermal growth factor receptor
  • Heat shock protein 27
  • Histone H3
  • Mitogen-activated protein kinase
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology

Cite this

EGFR-independent activation of p38 MAPK and EGFR-dependent activation of ERK1/2 are required for ROS-induced renal cell death. / Dong, Jing; Ramachandiran, Sampath; Tikoo, Kulbhushan; Jia, Zhe; Lau, Serrine; Monks, Terrence.

In: American Journal of Physiology - Renal Physiology, Vol. 287, No. 5 56-5, 11.2004.

Research output: Contribution to journalArticle

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T1 - EGFR-independent activation of p38 MAPK and EGFR-dependent activation of ERK1/2 are required for ROS-induced renal cell death

AU - Dong, Jing

AU - Ramachandiran, Sampath

AU - Tikoo, Kulbhushan

AU - Jia, Zhe

AU - Lau, Serrine

AU - Monks, Terrence

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AB - 2,3,5-Tris-(glutathion-S-yl)hydroquinone (TGHQ), a reactive metabolite of the nephrotoxicant hydroquinone, induces the ROS-dependent activation of MAPKs, followed by histone H3 phosphorylation and oncotic cell death in renal proximal tubule epithelial cells (LLC-PK1). Cell death and histone H3 phosphorylation are attenuated by pharmacological inhibition of p38 MAPK or ERK1/2 pathways. Because TGHQ, but not epidermal growth factor (EGF), induces histone H3 phosphorylation and cell death in LLC-PK1 cells, we hypothesized that there are differences in the mechanisms by which TGHQ and EGF induce activation of the EGF receptor (EGFR). We therefore compared the relative ability of TGHQ, H2O2, and EGF to activate EGFR and MAPKs and found that p38 MAPK activation is EGFR independent, whereas ERK1/2 activation occurs mainly through EGFR activation. TGHQ, H2O 2, and EGF induce different EGFR tyrosine phosphorylation profiles that likely influence the subsequent differential kinetics of MAPK activation. We next transfected LLC-PK1 cells with a dominant negative p38 MAPK-expressing plasmid (pcDNA3-DNp38). TGHQ failed to induce phosphorylation of p38 MAPK and its substrate, MK-2, in pcDNA3-DNp38-transfected cells, indicating loss of function of p38 MAPK. In untransfected, pcDNA3 or pcDNA3-p38 (native)-transfected LLC-PK1 cells, Hsp27 was intensively phosphorylated after TGHQ treatment, whereas in pcDNA3-DNp38-transfected cells, TGHQ failed to induce Hsp27 phosphorylation. Thus EGFR-independent p38 MAPK and EGFR-dependent ERK1/2 activation by TGHQ lead to the activation of two downstream signaling factors, i.e., histone H3 and Hsp27 phosphorylation, which have in common the potential ability to remodel chromatin.

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KW - Mitogen-activated protein kinase

KW - Reactive oxygen species

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