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氧化应激通路上的经典分子

Nrf1and Nrf2Play Distinct Roles in Activation of Antioxidant Response Element-dependent Genes*□S

Received for publication,June17,2008,and in revised form,September30,2008Published,JBC Papers in Press,September30,2008,DOI10.1074/jbc.M804597200 Makiko Ohtsuji‡§,Fumiki Katsuoka§,Akira Kobayashi§1,Hiroyuki Aburatani¶,John D.Hayesʈ,

and Masayuki Yamamoto‡§2

From the‡Graduate School of Comprehensive Human Sciences and Center for Tsukuba Advanced Research Alliance and Exploratory Research for Advanced Technology,Japan Science and Technology Corp.,1-1-1Tennoudai,Tsukuba305-8577,

§Department of Medical Biochemistry,Tohoku University Graduate School of Medicine,2-1Seiryo-cho,Aoba-ku,Sendai980-8575,¶Research Center for Advance Science and Technology,University of Tokyo,Tokyo153-8904,Japan,andʈBiomedical Research Institute,Ninewells Hospital and Medical School,University of Dundee,Dundee DD19SY,Scotland,United Kingdom

Nrf1is a member of the vertebrate Cap’n’Collar(CNC)tran-scription factor family that commonly contains a unique basic-leucine zipper domain.Among CNC family members,Nrf2is known to regulate a battery of antioxidant and xenobiotic-me-tabolizing enzyme genes through the antioxidant response ele-ment(ARE).Although Nrf1has also been shown to bind the ARE,it is unclear whether it plays a distinct role from Nrf2in regulating genes with this element.To address this issue in vivo, we generated mice bearing a hepatocyte-specific disruption of the Nrf1gene.Although Nrf2knock-out mice did not exhibit liver damage when they were maintained in an unstressed con-dition,hepatocyte-specific deletion of Nrf1caused liver damage resembling the human disease non-alcoholic steatohepatitis. Gene expression analysis revealed that the disruption of Nrf1 causes stress that activates a number of ARE-driven genes in an Nrf2-dependent manner,indicating that Nrf2cannot compen-sate completely for loss of Nrf1function in the liver.In contrast, expression of metallothionein-1and-2(MT1and MT2)genes, each of which harbors at least one ARE in its regulatory region, was decreased in the Nrf1-null mutant mice.Whereas Nrf1and Nrf2bound the MT1ARE with comparable affinity,Nrf1pref-erentially activated the reporter gene expression through the MT1ARE.This study has,thus,identified the first ARE-depend-ent gene that relies exclusively on Nrf1,suggesting that it plays a distinct functional role in regulating ARE-driven genes.

One of the unique features of transcription factors is that they can be categorized into structurally related groups(or fam-ilies)based on their DNA binding motifs.It appears that in addition to their common basic functions each member within a specific transcription factor family is likely to have acquired novel properties during its molecular evolution.Consequently, it is probable that a family of transcription factors collectively possesses abilities that enable individual members to fine-tune the expression of target genes during disparate biological pro-cesses through a common cis-acting element.

The Cap’n’Collar(CNC)3family of transcription factors has been well described.It comprises four closely related factors, Nrf1,Nrf2,Nrf3,and p45NF-E2(1,2).These CNC members contain a CNC domain juxtaposed with a conserved basic region-leucine zipper(bZip)domain.The CNC domain is rep-resented in an evolutionally distant homologue,SKN1in the nematode Caenorhabditis elegans(3).Although SKN1binds to DNA as a monomer,all vertebrate CNC members each het-erodimerize with one of three small Maf proteins,and the resulting heterodimers bind to the Maf recognition element (TGCTGA(G/C)TCAGCA)or related sequences.Because the vertebrate CNC members cannot bind to Maf recognition ele-ment sequences as monomers,small Maf proteins are indispen-sable partners of CNC bZip transcription factors(1,2).

The Maf recognition element-related sequence that is referred to as an antioxidant or electrophile response element (ARE/EpRE;hereafter designated ARE for simplicity)has been identified in the transcriptional regulatory regions of antioxi-dant and xenobiotic-metabolizing enzyme genes(1,2)and is thought to account for the coordinated up-regulation of these genes during oxidative stress.The ARE has been shown to recruit Nrf2and small Maf proteins(1,2).In Nrf2-null mutant mice the up-regulation of many antioxidant and detoxification enzyme genes has been found to be severely impaired(4).Nrf1 has also been shown to contribute to the regulation of ARE-de-pendent genes(5,6).Unlike Nrf2-null mice,Nrf1-null mice die by embryonic day13.5(E13.5)due to anemia(7).Furthermore, Nrf1:Nrf2compound mutant mice die by E11.5,suggesting that Nrf2can compensate,albeit partially,for the absence of Nrf1in embryonic mice(8).Based on the observation that an evolu-tionally distant CNC homolog SKN1also contributes to the induction of antioxidant genes(9),it can be hypothesized that

*This work was supported by grants from Exploratory Research for Advanced Technology-Japan Science and Technology Agency(to M.Y.)and the Min-istry of Education,Science,Sports,and Culture(to F.K.,A.K.,and M.Y.).The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked“advertise-ment”in accordance with18U.S.C.Section1734solely to indicate this fact.□S The on-line version of this article(available at http://www.wendangku.net/doc/b3c79071de80d4d8d05a4f0f.html)contains supplemental Table1.

1Present address:Dept.of Medical Life Systems,Doshisha University,Kyo-

tanabe,Kyoto610-0321Japan.

2To whom correspondence should be addressed:Dept.of Medical Biochem-istry,Tohoku University Graduate School of Medicine,2-1Seiryo-cho, Aoba-ku,Sendai980-8575,Japan.Tel.81-22-717-8084;Fax:81-22-717-8090;E-mail:masi@mail.tains.tohoku.ac.jp.3The abbreviations used are:CNC,Cap’n’Collar;NASH,non-alcoholic steato-hepatitis;ARE,antioxidant response element;ER,endoplasmic reticulum;

MT,metallothionein;RT,reverse transcription;NQO1,NAD(P)H dehydro-genase quinone1;GCLC,glutamate-cysteine ligase catalytic subunit;

HO-1,heme oxygenase-1;GSTP1,glutathione S-transferase␲1.

THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL.283,NO.48,pp.33554–33562,November28,2008©2008by The American Society for Biochemistry and Molecular Biology,Inc.Printed in the U.S.A.

33554JOURNAL OF BIOLOGICAL

氧化应激通路上的经典分子

CHEMISTRY VOLUME283•NUMBER48•NOVEMBER28,2008

at OCEAN UNIV on February 10, 2009 http://www.wendangku.net/doc/b3c79071de80d4d8d05a4f0f.html

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氧化应激通路上的经典分子

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