Anti-apoptotic effect of quercetin: Intervention in the JNK- and ERK-mediated apoptotic pathways
- 1 September 2000
- journal article
- Published by Elsevier BV in Kidney International
- Vol. 58 (3), 1078-1087
- https://doi.org/10.1046/j.1523-1755.2000.00265.x
Abstract
Bioflavonoid quercetin inhibits hydrogen peroxide (H2O2)-induced apoptosis via intervention in the activator protein 1 (AP-1)-mediated apoptotic pathway. In this report, we investigated molecular events involved in the anti-apoptotic effect of quercetin, focusing especially on its effects on the family of mitogen-activated protein (MAP) kinases.Cultured mesangial cells were exposed to H2O2, and activation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases (ERKs), and p38 MAP kinase was evaluated in the presence or absence of quercetin. Using pharmacological and genetic inhibitors, the roles for individual MAP kinases in H2O2-induced apoptosis were examined. Involvement of ERKs in the induction and activation of AP-1 was also investigated using Northern blot analysis and a reporter assay.Mesangial cells exposed to H2O2 exhibited rapid phosphorylation of JNK, ERKs, and p38 MAP kinase. Quercetin abrogated the activation of all three MAP kinases in response to H2O2. Pretreatment with MAP kinase kinase inhibitor PD098059 or JNK-c-Jun/AP-1 inhibitor curcumin attenuated the H2O2-induced apoptosis. In contrast, the p38 MAP kinase inhibitor SB203580 did not improve the cell survival. Consistently, transfection with dominant-negative mutants of ERK1 and ERK2 or a dominant-negative mutant of JNK inhibited H2O2-induced apoptosis. Transfection with a dominant-negative p38 MAP kinase did not attenuate the apoptotic process. Inhibition of ERKs by PD098059 suppressed induction of c-fos without affecting early induction of c-jun, leading to attenuated activation of AP-1 in response to H2O2.These results suggested that (1) activation of JNK and ERKs, but not p38 kinase, is required for the H2O2-induced apoptosis; and (2) suppression of the JNK-c-Jun/AP-1 pathway and the ERK-c-Fos/AP-1 pathway is involved in the anti-apoptotic effect of quercetin.Keywords
This publication has 41 references indexed in Scilit:
- Extracellular Signal-Regulated Kinase (ERK) Activity Is Required for TPA-Mediated Inhibition of Drug-Induced ApoptosisBiochemical and Biophysical Research Communications, 1998
- Three-dimensional matrix primes mesangial cells to down-regulation of α-smooth muscle actin via deactivation of CArG box elementsKidney International, 1998
- c-Jun/AP-1, but Not NF-κB, Is a Mediator for Oxidant-Initiated Apoptosis in Glomerular Mesangial CellsBiochemical and Biophysical Research Communications, 1997
- Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammationNature, 1997
- Induction of Apoptosis by ASK1, a Mammalian MAPKKK That Activates SAPK/JNK and p38 Signaling PathwaysScience, 1997
- Fibroblast Growth Factor-2 Suppression of Tumor Necrosis Factor α-Mediated Apoptosis Requires Ras and the Activation of Mitogen-activated Protein KinasePublished by Elsevier BV ,1996
- Signal Transduction Pathways Regulated by Mitogen-activated/Extracellular Response Kinase Kinase Kinase Induce Cell DeathJournal of Biological Chemistry, 1996
- Opposing Effects of ERK and JNK-p38 MAP Kinases on ApoptosisScience, 1995
- Reversion of v-H-ras-Trasformed NIH 3T3 Cells by Apigenin Through Inhibiting Mitogen-Activated Protein Kinase and Its Downstream OncogenesBiochemical and Biophysical Research Communications, 1995
- Gene transfer into the rat renal glomerulus via a mesangial cell vector: site-specific delivery, in situ amplification, and sustained expression of an exogenous gene in vivo.JCI Insight, 1994