Nuclear Receptor CAR Represses TNFα-Induced Cell Death by Interacting with the Anti-Apoptotic GADD45B 英文参考文献.docVIP

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Nuclear Receptor CAR Represses TNFα-Induced Cell Death by Interacting with the Anti-Apoptotic GADD45B 英文参考文献.doc

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Nuclear Receptor CAR Represses TNFα-Induced Cell Death by Interacting with the Anti-Apoptotic GADD45B 英文参考文献

NuclearReceptorCARRepressesTNFa-InducedCell DeathbyInteractingwiththeAnti-ApoptoticGADD45B YukioYamamoto1¤,RickMoore1,RichardA.Flavell2,BinfengLu3,MasahikoNegishi1* 1LaboratoryofReproductiveandDevelopmentalToxicology,NationalInstituteofEnvironmentalHealthSciences,NationalInstitutesofHealth,ResearchTrianglePark, North Carolina, United States of America, 2Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America, 3DepartmentofImmunology,UniversityofPittsburgh,SchoolofMedicine,Pittsburgh,Pennsylvania,UnitedStatesofAmerica Abstract Background: Phenobarbital (PB) is the most well-known among numerous non-genotoxic carcinogens that cause the developmentofhepatocellularcarcinoma(HCC).PBactivatesnuclearxenobioticreceptorConstitutiveActive/Androstane Receptor(CAR;NR1I3)andthisactivationisshowntodeterminePBpromotionofHCCinmice.Themolecularmechanismof CAR-mediatedtumorpromotion,however,remainselusiveatthepresenttime.HerewehaveidentifiedGrowthArrestand DNADamage-inducible45b(GADD45B)asanovelCARtarget,throughwhichCARrepressescelldeath. Methodology/PrincipalFindings:PBactivationofnuclearxenobioticreceptorCARisfoundtoinducetheGadd45bgenein mouseliverthroughoutthedevelopmentofHCCaswellasinlivertumors.GiventheknownfunctionofGADD45Basa factor that represses Mitogen-activated protein Kinase Kinase 7 -c-Jun N-terminal Kinase (MKK7-JNK) pathway-mediated apoptosis, we have now demonstrated that CAR interacts with GADD45B to repress Tumor Necrosis Factor a ( TNFa)- +/+ induced JNK1 phosphorylation as wellas cell death. Primary hepatocytes, prepared from Car ,Car2/2 ,Gadd45b +/+ and Gadd45b2/2 mice, were treated with TNFa and Actinomycin D to induce phosphorylation of JNK1 and cell death. Co- treatmentwiththeCARactivatingligandTCPOBOP(1,4bis[2-(3,5-dichloropyridyloxy)]benzene)hasresultedinrepressionof +/+ bothphosphorylationandcelldeathintheprimaryhepatocytesfromCar butnotCar2/2mice.RepressionbyTCPOBOP wasnotobservedinthoseprepa