The transcription factor Nrf2, which normally exists in an inactive state as a consequence of binding to a cytoskeleton-associated protein Keap1, can be activated by redox-dependent stimuli. Alteration of the Nrf2–Keap1 interaction enables Nrf2 to translocate to the nucleus, bind to the antioxidant-responsive element (ARE) and initiate the transcription of genes coding for detoxifying enzymes and cytoprotective proteins. This response is also triggered by a class of electrophilic compounds including polyphenols and plant-derived constituents. Recently, the natural antioxidants curcumin and caffeic acid phenethyl ester (CAPE) have been identified as potent inducers of haem oxygenase-1 (HO-1), a redox-sensitive inducible protein that provides protection against various forms of stress. Here, we show that in renal epithelial cells both curcumin and CAPE stimulate the expression of Nrf2 in a concentration- and time-dependent manner. This effect was associated with a significant increase in HO-1 protein expression and haem oxygenase activity. From several lines of investigation we also report that curcumin (and, by inference, CAPE) stimulates ho-1 gene activity by promoting inactivation of the Nrf2–Keap1 complex, leading to increased Nrf2 binding to the resident ho-1 AREs. Moreover, using antibodies and specific inhibitors of the mitogen-activated protein kinase (MAPK) pathways, we provide data implicating p38 MAPK in curcumin-mediated ho-1 induction. Taken together, these results demonstrate that induction of HO-1 by curcumin and CAPE requires the activation of the Nrf2/ARE pathway.
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Research Article|
May 01 2003
Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element
Elisabeth BALOGUN;
Elisabeth BALOGUN
∗Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, U.K.
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Martha HOQUE;
Martha HOQUE
∗Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, U.K.
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Pengfei GONG;
Pengfei GONG
†Department of Molecular Genetics, Ochsner Clinic Foundation, New Orleans, LA 70121, U.S.A.
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Erin KILLEEN;
Erin KILLEEN
†Department of Molecular Genetics, Ochsner Clinic Foundation, New Orleans, LA 70121, U.S.A.
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Colin J. GREEN;
Colin J. GREEN
∗Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, U.K.
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Roberta FORESTI;
Roberta FORESTI
∗Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, U.K.
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Jawed ALAM;
Jawed ALAM
†Department of Molecular Genetics, Ochsner Clinic Foundation, New Orleans, LA 70121, U.S.A.
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Roberto MOTTERLINI
Roberto MOTTERLINI
1
∗Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, U.K.
1To whom correspondence should be addressed (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
October 17 2002
Revision Received:
February 04 2003
Accepted:
February 06 2003
Accepted Manuscript online:
February 06 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 371 (3): 887–895.
Article history
Received:
October 17 2002
Revision Received:
February 04 2003
Accepted:
February 06 2003
Accepted Manuscript online:
February 06 2003
Citation
Elisabeth BALOGUN, Martha HOQUE, Pengfei GONG, Erin KILLEEN, Colin J. GREEN, Roberta FORESTI, Jawed ALAM, Roberto MOTTERLINI; Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J 1 May 2003; 371 (3): 887–895. doi: https://doi.org/10.1042/bj20021619
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