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J. Biol. Chem., Vol. 276, Issue 44, 41213-41223, November 2, 2001
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From the To explore the role of lipid
peroxidation (LPO) products in the initial phase of stress mediated
signaling, we studied the effect of mild, transient oxidative or heat
stress on parameters that regulate the cellular concentration of
4-hydroxynonenal (4-HNE). When K562 cells were exposed to mild heat
shock (42 °C, 30 min) or oxidative stress (50 µM
H2O2, 20 min) and allowed to recover for 2 h, there was a severalfold induction of hGST5.8, which catalyzes the
formation of glutathione-4-HNE conjugate (GS-HNE), and RLIP76, which
mediates the transport of GS-HNE from cells (Awasthi, S., Cheng, J.,
Singhal, S. S., Saini, M. K., Pandya, U., Pikula, S., Bandorowicz-Pikula, J., Singh, S. V., Zimniak, P., and
Awasthi, Y. C. (2000) Biochemistry 39, 9327-9334).
Enhanced LPO was observed in stressed cells, but the major antioxidant
enzymes and HSP70 remained unaffected. The stressed cells showed higher
GS-HNE-conjugating activity and increased efflux of GS-HNE.
Stress-pre-conditioned cells with induced hGST5.8 and RLIP76 acquired
resistance to 4-HNE and H2O2-mediated apoptosis
by suppressing a sustained activation of c-Jun N-terminal kinase and
caspase 3. The protective effect of stress pre-conditioning against
apoptosis was abrogated by coating the cells with anti-RLIP76 IgG,
which inhibited the efflux of GS-HNE from cells, indicating that the
cells acquired resistance to apoptosis by metabolizing and excluding
4-HNE at a higher rate. Induction of hGST5.8 and RLIP76 by mild,
transient stress and the resulting resistance of stress-pre-conditioned
cells to apoptosis appears to be a general phenomenon since it was not
limited to K562 cells but was also evident in lung cancer cells, H-69,
H-226, human leukemia cells, HL-60, and human retinal pigmented
epithelial cells. These results strongly suggest a role of LPO
products, particularly 4-HNE, in the initial phase of stress mediated signaling.
Accelerated Metabolism and Exclusion of
4-Hydroxynonenal through Induction of RLIP76 and hGST5.8 Is an Early
Adaptive Response of Cells to Heat and Oxidative Stress*
,
,
,
,
,
,
**
Department of Human Biological Chemistry and
Genetics, University of Texas Medical Branch, Galveston, Texas
77555-1067, § Department of Chemistry and Biochemistry,
University of Texas, Arlington, Texas 76019-0065, ¶ Department of
Pharmacology and University of Pittsburgh Cancer Institute, University
of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, and
Department of Internal Medicine and Department of Biochemistry
and Molecular Biology, University of Arkansas for Medical Sciences and
Central Arkansas Veterans Healthcare System,
Little Rock, Arkansas 72205
*
This work was supported in part by National Institutes of
Health Grants EY 04396, CA 27967 (to Y. C. A.), CA 77495 (to S. A.),
CA 76348 (to S. V. S.), and ES 07804 (to P. Z.) and by a Veterans
Affairs Merit Review grant (to P. Z.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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