The FASEB Journal, Vol 10, 709-720, Copyright © 1996 by The Federation of American Societies for Experimental Biology

REVIEWS

Antioxidant and redox regulation of gene transcription

CK Sen and L Packer
Department of Molecular and Cell Biology, University of California at Berkeley, California 94720-3200, USA.

Reactive oxygen species (ROS) are implicated in the pathogenesis of a wide variety of human diseases. Recent evidence suggests that at moderately high concentrations, certain forms of ROS such as H202 may act as signal transduction messengers. To develop a better understanding of the exact mechanisms that underlie ROS-dependent disorders in biological systems, recent studies have investigated the regulation of gene expression by oxidants, antioxidants, and other determinants of the intracellular reduction-oxidation (redox) state. At least two well-defined transcription factors, nuclear factor (NF) kappa B and activator protein (AP) -1 have been identified to be regulated by the intracellular redox state. The regulation of gene expression by oxidants, antioxidants, and the redox state has emerged as a novel subdiscipline in molecular biology that has promising therapeutic implications. Binding sites of the redox-regulated transcription factors NF-kappa B and AP-1 are located in the promoter region of a large variety of genes that are directly involved in the pathogenesis of diseases, e.g., AIDS, cancer, atherosclerosis and diabetic complications. Biochemical and clinical studies have indicated that antioxidant therapy may be useful in the treatment of disease. Critical steps in the signal transduction cascade are sensitive to oxidants and antioxidants. Many basic events of cell regulation such as protein phosphorylation and binding of transcription factors to consensus sites on DNA are driven by physiological oxidant-antioxidant homeostasis, especially by the thiol-disulfide balance. Endogenous glutathione and thioredoxin systems, and the exogenous lipoate-dihydrolipoate couple may therefore be considered to be effective regulators of redox- sensitive gene expression. The efficacy of different antioxidants to favorably influence the molecular mechanisms implicated in human disease should be a critical determinant of its selection for clinical studies.

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				T. Nakatani, N. Tsuboyama-Kasaoka, M. Takahashi, S. Miura, and O. Ezaki Mechanism for Peroxisome Proliferator-activated Receptor-alpha Activator-induced Up-regulation of UCP2 mRNA in Rodent Hepatocytes J. Biol. Chem., March 8, 2002; 277(11): 9562 - 9569. [Abstract] [Full Text] [PDF]

				K. Ohta, K. Nakayama, T. Kurokawa, T. Kikuchi, and N. Yoshimura Inhibitory Effects of Pyrrolidine Dithiocarbamate on Endotoxin-Induced Uveitis in Lewis Rats Invest. Ophthalmol. Vis. Sci., March 1, 2002; 43(3): 744 - 750. [Abstract] [Full Text] [PDF]

				J. M. Hansen, K. K. Harris, M. A. Philbert, and C. Harris Thalidomide Modulates Nuclear Redox Status and Preferentially Depletes Glutathione in Rabbit Limb versus Rat Limb J. Pharmacol. Exp. Ther., March 1, 2002; 300(3): 768 - 776. [Abstract] [Full Text] [PDF]

				P. A. Havre, S. O'Reilly, J. J. McCormick, and D. E. Brash Transformed and Tumor-derived Human Cells Exhibit Preferential Sensitivity to the Thiol Antioxidants, N-Acetyl Cysteine and Penicillamine Cancer Res., March 1, 2002; 62(5): 1443 - 1449. [Abstract] [Full Text] [PDF]

				M. J. Whitekus, N. Li, M. Zhang, M. Wang, M. A. Horwitz, S. K. Nelson, L. D. Horwitz, N. Brechun, D. Diaz-Sanchez, and A. E. Nel Thiol Antioxidants Inhibit the Adjuvant Effects of Aerosolized Diesel Exhaust Particles in a Murine Model for Ovalbumin Sensitization J. Immunol., March 1, 2002; 168(5): 2560 - 2567. [Abstract] [Full Text] [PDF]

				B. L. Halvorsen, K. Holte, M. C. W. Myhrstad, I. Barikmo, E. Hvattum, S. F. Remberg, A.-B. Wold, K. Haffner, H. Baugerod, L. F. Andersen, et al. A Systematic Screening of Total Antioxidants in Dietary Plants J. Nutr., March 1, 2002; 132(3): 461 - 471. [Abstract] [Full Text] [PDF]

				H. Guo, C. Q. Cai, and P. C. Kuo Hepatocyte Nuclear Factor-4alpha Mediates Redox Sensitivity of Inducible Nitric-oxide Synthase Gene Transcription J. Biol. Chem., February 8, 2002; 277(7): 5054 - 5060. [Abstract] [Full Text] [PDF]

				L. E. Otterbein and A. M. K. Choi The Saga of Leucine Zippers Continues . In Response to Oxidative Stress Am. J. Respir. Cell Mol. Biol., February 1, 2002; 26(2): 161 - 163. [Full Text] [PDF]

				Y. K. Kim, M.-S. Lee, S. M. Son, I. J. Kim, W. S. Lee, B. Y. Rhim, K. W. Hong, and C. D. Kim Vascular NADH Oxidase Is Involved in Impaired Endothelium-Dependent Vasodilation in OLETF Rats, a Model of Type 2 Diabetes Diabetes, February 1, 2002; 51(2): 522 - 527. [Abstract] [Full Text] [PDF]

				A. Mittur, A. W. Wolkoff, and N. Kaplowitz The Thiol Sensitivity of Glutathione Transport in Sidedness-Sorted Basolateral Liver Plasma Membrane and in Oatp1-Expressing HeLa Cell Membrane Mol. Pharmacol., February 1, 2002; 61(2): 425 - 435. [Abstract] [Full Text] [PDF]

				F. TOSETTI, N. FERRARI, S. DE FLORA, and A. ALBINI Angioprevention': angiogenesis is a common and key target for cancer chemopreventive agents FASEB J, January 1, 2002; 16(1): 2 - 14. [Abstract] [Full Text] [PDF]

				G. F. Davies, P. J. McFie, R. L. Khandelwal, and W. J. Roesler Unique Ability of Troglitazone to Up-Regulate Peroxisome Proliferator-Activated Receptor-gamma Expression in Hepatocytes J. Pharmacol. Exp. Ther., January 1, 2002; 300(1): 72 - 77. [Abstract] [Full Text] [PDF]

				W. Droge Free Radicals in the Physiological Control of Cell Function Physiol Rev, January 1, 2002; 82(1): 47 - 95. [Abstract] [Full Text] [PDF]

				J. R. Hoidal Reactive Oxygen Species and Cell Signaling Am. J. Respir. Cell Mol. Biol., December 1, 2001; 25(6): 661 - 663. [Full Text] [PDF]

				A. Levine, B. Belenghi, H. Damari-Weisler, and D. Granot Vesicle-associated Membrane Protein of Arabidopsis Suppresses Bax-induced Apoptosis in Yeast Downstream of Oxidative Burst J. Biol. Chem., November 30, 2001; 276(49): 46284 - 46289. [Abstract] [Full Text] [PDF]

				X. Zhang, J.-J. Jiao, B. R. Bhavnani, and S.-P. Tam Regulation of human apolipoprotein A-I gene expression by equine estrogens J. Lipid Res., November 1, 2001; 42(11): 1789 - 1800. [Abstract] [Full Text] [PDF]

				A. Karube-Harada, N. Sugino, S. Kashida, S. Takiguchi, H. Takayama, Y. Yamagata, Y. Nakamura, and H. Kato Induction of manganese superoxide dismutase by tumour necrosis factor-{alpha} in human endometrial stromal cells Mol. Hum. Reprod., November 1, 2001; 7(11): 1065 - 1072. [Abstract] [Full Text] [PDF]

				C. Huang, J. Li, M. Costa, Z. Zhang, S. S. Leonard, V. Castranova, V. Vallyathan, G. Ju, and X. Shi Hydrogen Peroxide Mediates Activation of Nuclear Factor of Activated T Cells (NFAT) by Nickel Subsulfide Cancer Res., November 1, 2001; 61(22): 8051 - 8057. [Abstract] [Full Text] [PDF]

				C. Huang, J. Li, M. Ding, S. S. Leonard, L. Wang, V. Castranova, V. Vallyathan, and X. Shi UV Induces Phosphorylation of Protein Kinase B (Akt) at Ser-473 and Thr-308 in Mouse Epidermal Cl 41 Cells through Hydrogen Peroxide J. Biol. Chem., October 19, 2001; 276(43): 40234 - 40240. [Abstract] [Full Text] [PDF]