Molecular Mechanisms of Nrf2-Mediated Antioxidant Response

被引：660

作者：

Li, Wenge ^{[1
]}

Kong, Ah-Ng ^{[1
]}

机构：

[1] Rutgers State Univ, Ernest Mario Sch Pharm, Dept Pharmaceut, Piscataway, NJ 08854 USA

来源：

MOLECULAR CARCINOGENESIS | 2009年 / 48卷 / 02期

关键词：

Nrf2; Keap1; redox; TRANSCRIPTION FACTOR NRF2; MEDIATED GENE-EXPRESSION; NUCLEAR EXPORT SIGNAL; PROTEIN-KINASE-C; SUBSTRATE ADAPTER PROTEIN; UBIQUITIN LIGASE COMPLEX; CREB-BINDING-PROTEIN; CUL3-BASED E3 LIGASE; N-TERMINAL DOMAIN; OXIDATIVE STRESS;

D O I：

10.1002/mc.20465

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Nrf2 is the key transcription factor regulating the antioxidant response. Nrf2 signaling is repressed by Keap1 at basal condition and induced by oxidative stress. Keap1 is recently identified as a Cullin 3-dependent substrate adaptor protein. A two-sites binding "hinge & latch" model vividly depicts how Keap1 can efficiently present Nrf2 as substrate for ubquitination. Oxidative perturbation can impede Keap1-mediated Nrf2 ubiquitination but fail to disrupt Nrf2/Keap1 binding. Nrf2 per se is a redox-sensitive transcription factor. A new Nrf2-mediated redox signaling model is proposed based on these new discoveries. Free floating Nrf2 protein functions as a redox-sensitive probe. Keap1 instead functions as a gate keeper to control the availability of Nrf2 probes and thus regulates the overall sensitivity of the redox signaling. (C) 2008 Wiley-Liss, Inc.

引用

页码：91 / 104

页数：14

共 121 条

[1] Site-directed mutagenesis of cysteine to serine in the DNA binding region of Nrf2 decreases its capacity to upregulate antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene [J].

Bloom, D ;

Dhakshinamoorthy, S ;

Jaiswal, AK .

ONCOGENE, 2002, 21 (14) :2191-2200

[2] Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element-mediated NAD(P)H:quinone oxidoreductase-1 gene expression [J].

Bloom, DA ;

Jaiswal, AK .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (45) :44675-44682

[3] ROLE OF ATP AND DISULFIDE BONDS DURING PROTEIN FOLDING IN THE ENDOPLASMIC-RETICULUM [J].

BRAAKMAN, I ;

HELENIUS, J ;

HELENIUS, A .

NATURE, 1992, 356 (6366) :260-262

[4] Mutual cross-talk between reactive oxygen species and nuclear factor-kappa B: molecular basis and biological significance [J].

Bubici, C. ;

Papa, S. ;

Dean, K. ;

Franzoso, G. .

ONCOGENE, 2006, 25 (51) :6731-6748

[5] CLONING OF NRF1, AN NF-E2-RELATED TRANSCRIPTION FACTOR, BY GENETIC SELECTION IN YEAST [J].

CHAN, JY ;

HAN, XL ;

KAN, YW .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (23) :11371-11375

[6] Dietary cancer-chemopreventive compounds: from signaling and gene expression to pharmacological effects [J].

Chen, C ;

Kong, ANT .

TRENDS IN PHARMACOLOGICAL SCIENCES, 2005, 26 (06) :318-326

[7] Induction of detoxifying enzymes by garlic organosulfur compounds through transcription factor Nrf2: Effect of chemical structure and stress signals [J].

Chen, C ;

Pung, D ;

Leong, V ;

Hebbar, V ;

Shen, GX ;

Nair, S ;

Li, W ;

Kong, ANT .

FREE RADICAL BIOLOGY AND MEDICINE, 2004, 37 (10) :1578-1590

[8] Role of Gα12 and gα13 as novel switches for the activity of Nrf2, a key antioxidative transcription factor [J].

Cho, Min Kyung ;

Kim, Won Dong ;

Ki, Sung Hwan ;

Hwang, Jong-IK ;

Choi, Sangdun ;

Lee, Chang Ho ;

Kim, Sang Geon .

MOLECULAR AND CELLULAR BIOLOGY, 2007, 27 (17) :6195-6208

[9] DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2 [J].

Clements, Casey M. ;

McNally, Richard S. ;

Conti, Brian J. ;

Mak, Tak W. ;

Ting, Jenny P-Y. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (41) :15091-15096

[10] Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival [J].

Cullinan, SB ;

Zhang, D ;

Hannink, M ;

Arvisais, E ;

Kaufman, RJ ;

Diehl, JA .

MOLECULAR AND CELLULAR BIOLOGY, 2003, 23 (20) :7198-7209

← 1 2 3 4 5 6 7 8 9 10 →