Roles of the ubiquitin ligase CUL4B and ADP-ribosyltransferase TiPARP in TCDD-induced nuclear export and proteasomal degradation of the transcription factor AHR

Abstract

The aryl hydrocarbon receptor (AHR) is a transcription factor activated by exogenous halogenated polycyclic aromatic hydrocarbon compounds, including the environmental toxin TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and naturally occurring dietary and endogenous compounds. The activated AHR enhances transcription of specific genes including phase I and phase II metabolism enzymes and other targets genes such as the TCDD-inducible poly(ADP-ribose) polymerase (TiPARP). The regulation of AHR activation is a dynamic process: immediately after transcriptional activation of the AHR by TCDD, the AHR is exported from the nucleus to the cytoplasm where it is subjected to proteasomal degradation. However, the mechanisms regulating AHR degradation are not well understood. Here, we studied the role of two enzymes reported to enhance AHR breakdown: the cullin 4B (CUL4B)AHR complex, an E3 ubiquitin ligase that targets the AHR and other proteins for ubiquitination, and TiPARP, which targets proteins for ADP-ribosylation, a posttranslational modification that can increase susceptibility to degradation. Using a WT mouse embryonic fibroblast (MEF) cell line and an MEF cell line in which CUL4B has been deleted (MEFCul4b-null), we discovered that loss of CUL4B partially prevented AHR degradation after TCDD exposure, while knocking down TiPARP in MEFCul4b-null cells completely abolished AHR degradation upon TCDD treatment. Increased TCDD-activated AHR protein levels in MEFCul4b-null and MEFCul4b-null cells in which TiPARP was knocked down led to enhanced AHR transcriptional activity, indicating that CUL4B and TiPARP restrain AHR action. This study reveals a novel function of TiPARP in controlling TCDD-activated AHR nuclear export and subsequent proteasomal degradation. The aryl hydrocarbon receptor (AHR) is a transcription factor activated by exogenous halogenated polycyclic aromatic hydrocarbon compounds, including the environmental toxin TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and naturally occurring dietary and endogenous compounds. The activated AHR enhances transcription of specific genes including phase I and phase II metabolism enzymes and other targets genes such as the TCDD-inducible poly(ADP-ribose) polymerase (TiPARP). The regulation of AHR activation is a dynamic process: immediately after transcriptional activation of the AHR by TCDD, the AHR is exported from the nucleus to the cytoplasm where it is subjected to proteasomal degradation. However, the mechanisms regulating AHR degradation are not well understood. Here, we studied the role of two enzymes reported to enhance AHR breakdown: the cullin 4B (CUL4B)AHR complex, an E3 ubiquitin ligase that targets the AHR and other proteins for ubiquitination, and TiPARP, which targets proteins for ADP-ribosylation, a posttranslational modification that can increase susceptibility to degradation. Using a WT mouse embryonic fibroblast (MEF) cell line and an MEF cell line in which CUL4B has been deleted (MEFCul4b-null), we discovered that loss of CUL4B partially prevented AHR degradation after TCDD exposure, while knocking down TiPARP in MEFCul4b-null cells completely abolished AHR degradation upon TCDD treatment. Increased TCDD-activated AHR protein levels in MEFCul4b-null and MEFCul4b-null cells in which TiPARP was knocked down led to enhanced AHR transcriptional activity, indicating that CUL4B and TiPARP restrain AHR action. This study reveals a novel function of TiPARP in controlling TCDD-activated AHR nuclear export and subsequent proteasomal degradation. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin), a byproduct of incineration and other industrial processes, is a ubiquitous environmental contaminant whose toxic effects, widely observed in different species, include developmental defects, cancer, a wasting syndrome, hepatosteatosis, thymus involution, and dysregulation of immune responses (1Poland A. Knutson J.C. 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: Examination of the mechanism of toxicity.Annu. Rev. Pharmacol. Toxicol. 1982; 22: 517-554Crossref PubMed Scopus (2291) Google Scholar, 2Diani-Moore S. Shoots J. Singh R. Zuk J.B. Rifkind A.B. NAD(+) loss, a new player in AhR biology: Prevention of thymus atrophy and hepatosteatosis by NAD(+) repletion.Sci. Rep. 2017; 7: 2268Crossref PubMed Scopus (25) Google Scholar, 3Bock K.W. Kohle C. 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Exactly the same but different: Promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor.Toxicol. Sci. 2011; 124: 1-22Crossref PubMed Scopus (482) Google Scholar, 7Gutierrez-Vazquez C. Quintana F.J. Regulation of the immune response by the aryl hydrocarbon receptor.Immunity. 2018; 48: 19-33Abstract Full Text Full Text PDF PubMed Scopus (278) Google Scholar). AHR transcriptional activation is a dynamic process: an inactive AHR that is not bound to a ligand (either endogenous or exogenous) resides in the cytoplasm in a complex with several different proteins (i.e., heat shock protein 90, AHR-interacting protein, and AHR-activated 9 protein (8Beischlag T.V. Luis Morales J. Hollingshead B.D. Perdew G.H. The aryl hydrocarbon receptor complex and the control of gene expression.Crit. Rev. Eukaryot. Gene Expr. 2008; 18: 207-250Crossref PubMed Scopus (519) Google Scholar)). Upon ligand binding, the AHR moves into the nucleus where it dimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT) protein to produce an AHR/ARNT heterodimer that activates gene transcription by binding to dioxin-responsive elements, specific DNA sequences in the promoter regions of AHR-responsive genes, that is, phase I (oxidation) and phase II (conjugation) drug-metabolism enzymes (including cytochrome P450 enzymes in the CYP1A and CYP1B families (mammalian cyp1a1, cyp1a2, and cyp1b1), and many other targets including TCDD-inducible poly(ADP-ribose) polymerase (TiPARP) (also known as PARP7 and ARTD14)), and the aryl hydrocarbon receptor repressor (8Beischlag T.V. Luis Morales J. Hollingshead B.D. Perdew G.H. The aryl hydrocarbon receptor complex and the control of gene expression.Crit. Rev. Eukaryot. Gene Expr. 2008; 18: 207-250Crossref PubMed Scopus (519) Google Scholar, 9Ma Q. Baldwin K.T. Renzelli A.J. McDaniel A. Dong L. TCDD-inducible poly(ADP-ribose) polymerase: A novel response to 2,3,7,8-tetrachlorodibenzo-p-dioxin.Biochem. Biophys. Res. Commun. 2001; 289: 499-506Crossref PubMed Scopus (111) Google Scholar). Simultaneously with activation of AHR-mediated gene transcription, the AHR begins to be degraded and AHR levels decline (10Pollenz R.S. The mechanism of AH receptor protein down-regulation (degradation) and its impact on AH receptor-mediated gene regulation.Chem. Biol. Interact. 2002; 141: 41-61Crossref PubMed Scopus (183) Google Scholar). Proteolytic degradation of transcription factors is a known mechanism for regulating signaling pathways (11Pahl H.L. Baeuerle P.A. Control of gene expression by proteolysis.Curr. Opin. Cell Biol. 1996; 8: 340-347Crossref PubMed Scopus (139) Google Scholar), and although the phenomenon of AHR degradation has been known for many years, the process by which it occurs is not well understood. Through the late 1990s and early 2000s, a series of articles by Richard Pollenz et into the of the after AHR ligand activation and to the a nuclear export on the of the AHR its from the nucleus to the cytoplasm where the AHR is degraded via the (10Pollenz R.S. The mechanism of AH receptor protein down-regulation (degradation) and its impact on AH receptor-mediated gene regulation.Chem. Biol. Interact. 2002; 141: 41-61Crossref PubMed Scopus (183) Google Scholar, Pollenz R.S. hydrocarbon receptor into the nucleus ligand binding is degraded via the nuclear Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, R.S. of the complex nuclear export and aryl hydrocarbon receptor-mediated gene Biol. PubMed Scopus Google Scholar). of the was to increase the levels of the complex in the nucleus to of levels Q. Baldwin K.T. degradation of aryl hydrocarbon receptor by the of the transcription and DNA binding of Biol. Full Text Full Text PDF PubMed Scopus Google Scholar), indicating that AHR degradation is a mechanism for the transcriptional of the E3 ubiquitin ligase of specific for proteasomal degradation and are in many and J. and of the cullin E3 ligase proteins and PubMed Scopus Google Scholar). et A. M. K. S. A. K. S. receptor is a E3 ubiquitin PubMed Scopus Google identified the AHR as an E3 ubiquitin of an ligase 4B complex where CUL4B as a the different and AHR as the for proteins for A. M. K. S. A. K. S. receptor is a E3 ubiquitin PubMed Scopus Google Scholar, K. J. S. Pollenz R.S. M. L. S. hydrocarbon receptor in with Sci. S. A. PubMed Scopus Google Scholar, Q. Q. hydrocarbon receptor by ubiquitin ligase to for proteasomal Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). CUL4B with the AHR via its A. M. K. S. A. K. 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This mechanism to activated AHR the AHR gene TiPARP, a was to of the activated knocking TiPARP AHR protein levels in a mouse embryonic fibroblast (MEF) cell line and an by enhanced AHR transcriptional by TCDD S. A. L. A. L. J. of the to and Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, L. L. S. J.P. J. 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase is a and repressor of aryl hydrocarbon receptor Res. PubMed Scopus Google and a role for TiPARP in regulating AHR levels and the reported we to the of loss of CUL4B and TiPARP on activated AHR and to two factors the AHR after its ligand we TCDD as a ligand to the MEF cell line in which the 4B gene been knocked (MEFCul4b-null), and to down study the of the E3 ligase complex to AHR degradation by TCDD, we an MEFCul4b-null cell line was from a CUL4B mouse in L. L. L. role of the CUL4B ubiquitin ligase in mouse Res. 22: PubMed Scopus Google Scholar). WT and MEFCul4b-null cells with several of TCDD and or for The of AHR levels by TCDD with or was in WT cells and in MEFCul4b-null cells indicating that loss of CUL4B but not AHR degradation. also that CUL4B is and not by TCDD in the WT MEF cell line while CUL4B protein is in MEFCul4b-null cell study the in AHR after its activation by TCDD in with AHR transcriptional activity, we a in WT MEF and MEFCul4b-null cells with TCDD for and and we AHR levels and a of activation J. role of AhR in the expression of toxic by Biophys. PubMed Scopus Google Scholar, A.B. F.J. of aryl hydrocarbon receptor-mediated of the enzymes in environmental and Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). in that after TCDD levels of the AHR with in WT MEF cells by and with AHR degradation occurring the AHR is activated by MEFCul4b-null AHR protein after TCDD with and that is AHR degradation with the loss of CUL4B cell of AHR levels with AHR levels TCDD that levels by TCDD also in a and in MEFCul4b-null cells WT MEF MEFCul4b-null WT that AHR degradation with loss of CUL4B to AHR transcriptional that the AHR was not by TCDD in with a by and Pollenz Pollenz R.S. and of aryl hydrocarbon receptor and gene Pharmacol. 2002; PubMed Scopus Google Scholar), was by CUL4B the in AHR protein levels observed in MEFCul4b-null cells by TCDD was to proteasomal degradation. that with TCDD and the not prevented the of AHR levels by TCDD in WT cells but also prevented AHR degradation in MEFCul4b-null indicating that the is for the of AHR protein levels by TCDD also in the of the ubiquitin The AHR gene TiPARP has been reported to AHR degradation via its L. L. S. J.P. J. 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase is a and repressor of aryl hydrocarbon receptor Res. PubMed Scopus Google Scholar), and has been to for and proteasomal degradation of proteins R. and molecular to 2017; PubMed Scopus Google Scholar). we TiPARP can to AHR degradation after TCDD in the of CUL4B or CUL4B is for TiPARP action. that TiPARP by AHR protein levels in TCDD WT MEF and MEFCul4b-null cells with cells with TCDD indicating that TiPARP can degradation of the AHR in the of The of TiPARP and loss of CUL4B in MEFCul4b-null AHR protein levels TiPARP or loss of CUL4B indicating that TiPARP and CUL4B have in AHR degradation. AHR protein levels after TiPARP in WT MEF and MEFCul4b-null cells by transcriptional of the as by levels of the AhR gene a in levels the TiPARP for the AHR protein levels in TCDD MEFCul4b-null cells AHR protein levels in control MEFCul4b-null cells TiPARP we with a of the TiPARP gene in MEFCul4b-null cells as in the loss of TiPARP, we several (including several and a that TiPARP S. S. Rifkind A.B. hydrocarbon receptor activation by targets for via poly(ADP-ribose) polymerase Biol. Full Text Full Text PDF PubMed Scopus (25) Google but of not the of the loss of TiPARP protein by we the of in the TiPARP gene by of of the TiPARP gene The that we a cell line that of to a the of the TiPARP gene WT MEFCul4b-null and MEFCul4b-null cells in which TiPARP was knocked down with TCDD or for or and by to TCDD on AHR protein levels in cell that after of TCDD AHR protein levels by in the WT MEF while the AHR by in the MEFCul4b-null in TCDD not AHR protein of the AHR protein was in WT MEF cells and was by in MEFCul4b-null in AhR degradation by TCDD was completely AHR protein levels with AHR transcriptional as and in cells MEFCul4b-null cells after TCDD that AHR degradation by TCDD is completely abolished in the of CUL4B and TiPARP and that TiPARP AHR degradation in the of the AHR protein levels with the loss of CUL4B and TiPARP have other of AHR The of the is of the line of in the cell and Rev. 2001; PubMed Scopus Google Scholar). has been reported that AHR activation an by TiPARP in the cell S. M. A. M. J. A. aryl hydrocarbon receptor signaling I Immunol. PubMed Scopus Google Scholar). TiPARP was to and the of the which is a of S. M. A. M. J. A. aryl hydrocarbon receptor signaling I Immunol. PubMed Scopus Google Scholar). we the of TCDD on the in WT and the cell with a that to the of by of the cells with TCDD or for that in WT the of levels control and TCDD not in control and MEFCul4b-null of TiPARP and CUL4B the of by in control and with a role for TiPARP in by TCDD-activated WT MEF cells with with cells with a control indicating that not TCDD-activated AHR transcriptional in The that loss of CUL4B or TiPARP can have as by in and Pollenz Pollenz R.S. hydrocarbon receptor into the nucleus ligand binding is degraded via the nuclear Biol. 1999; Full Text Full Text PDF PubMed Scopus Google and cell that the TCDD-activated AHR export from the nucleus to the cytoplasm to be degraded by the the of protein export from the nucleus on AHR WT MEF the cells with or TCDD and different of an of (also known as B. M. S. M. of nuclear export by binding to Cell Res. PubMed Scopus Google Scholar), which the nuclear export of proteins including the AHR Pollenz R.S. hydrocarbon receptor into the nucleus ligand binding is degraded via the nuclear Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). led to of the AHR in the nucleus in WT MEF cells in a AHR protein levels in the with the of AHR nuclear export we studied the of the AHR by in WT MEF cells with the or TCDD with or a that not cell 4B that the AHR resides in the cytoplasm of control cells and was by TCDD by The AHR protein in the as by the of the AHR and the nuclear with TCDD the AHR in the nucleus with the in and by and Pollenz Pollenz R.S. hydrocarbon receptor into the nucleus ligand binding is degraded via the nuclear Biol. 1999; Full Text Full Text PDF PubMed Scopus Google reported that nuclear export to of the AHR in the study the of CUL4B and TiPARP in AHR nuclear we MEFCul4b-null and cells with WT MEF cells with or TCDD for and nuclear and that AHR protein levels by in the nuclear of MEFCul4b-null cells with the control MEFCul4b-null and the loss of TiPARP in to the loss of CUL4B in cells a of the AHR in the nucleus that in the of WT the AHR was was a in the of MEFCul4b-null and cells cell the by by and that TCDD not to AHR degradation in and that the AHR was in the nucleus it was in the cytoplasm in with the in and which that the AHR is not degraded and in the nucleus after TCDD in of nuclear export by on AHR levels after TCDD in indicating that the loss of CUL4B and TiPARP is to the nuclear export of the that in the of CUL4B and TiPARP, the AHR is not exported from the nucleus to the cytoplasm and in the the of the role of TiPARP in regulating AHR nuclear export and we WT MEF cells and as for to that we a cell line that of to the of the TiPARP gene and WT MEF cells with or TCDD that cells AHR levels WT that AHR protein in the nucleus of AHR levels in cells by and and also AHR levels and in the of TiPARP by CUL4B in cells with a CUL4B or and with the or TCDD that CUL4B a of AHR levels in and nuclear of cells after TCDD CUL4B was the levels of endogenous CUL4B in WT cells in and that TiPARP has a CUL4B in TCDD-activated AHR nuclear export and proteasomal degradation. AHR which occurs after TCDD is an in regulating AHR signaling (10Pollenz R.S. The mechanism of AH receptor protein down-regulation (degradation) and its impact on AH receptor-mediated gene regulation.Chem. Biol. Interact. 2002; 141: 41-61Crossref PubMed Scopus (183) Google Scholar, Pollenz R.S. hydrocarbon receptor into the nucleus ligand binding is degraded via the nuclear Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, R.S. of the complex nuclear export and aryl hydrocarbon receptor-mediated gene Biol. PubMed Scopus Google Scholar). Using MEF cell we studied the of two factors that AHR protein the E3 ubiquitin ligase complex and the AHR the that are as CUL4B and TiPARP to AHR protein TiPARP has a CUL4B in AHR proteasomal and loss of CUL4B and TiPARP completely AHR degradation. that loss of CUL4B and TiPARP can have on AHR transcriptional and action. of the AHR from the nucleus to the cytoplasm is for AHR proteasomal degradation (10Pollenz R.S. The mechanism of AH receptor protein down-regulation (degradation) and its impact on AH receptor-mediated gene regulation.Chem. Biol. Interact. 2002; 141: 41-61Crossref PubMed Scopus (183) Google Scholar). that loss of TiPARP of the TCDD-activated AHR in the indicating that TiPARP in the regulation of AHR nuclear The AHR a nuclear in the and in the and in other A. Hollingshead B. Perdew G.H. The of the nuclear of the Ah receptor and transcriptional Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, K. and export of the aryl hydrocarbon Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, of nuclear export sequences of the Biol. 2001; Full Text Full Text PDF PubMed Scopus (25) Google Scholar, B. M. of of and J. Sci. Scopus Google Scholar). of the activated AHR the to AHR nuclear export L. K. A. S. controlling and DNA in the AHR transcriptional Sci. S. A. 2017; PubMed Scopus Google Scholar), and posttranslational of the AHR a role in TiPARP is a of the enzymes which proteins for ADP-ribosylation, to different R. and molecular to 2017; PubMed Scopus Google Scholar, and Scopus Google Scholar), including or of protein nuclear export M. The poly(ADP-ribose) in PubMed Scopus Google Scholar, G. and role for PubMed Scopus Google Scholar). et A. C. G. L. S. L. A. J. of TCDD-inducible polymerase J. 2018; PubMed Scopus Google in that TiPARP can the AHR including the AHR which has been reported to a regulating the and the AHR nuclear export to the cytoplasm A. J. J. C. A. The of the AHR nuclear and Rep. PubMed Scopus Google Scholar, R.S. of endogenous protein on the and of the endogenous mouse receptor in the and of Pharmacol. 2006; PubMed Scopus Google Scholar). be of to the role of the specific in AHR nuclear by enzymes has been reported to proteins for and proteasomal degradation J.P. B.D. is a poly(ADP-ribose) E3 ubiquitin ligase that DNA Sci. S. A. 2011; PubMed Scopus Google Scholar, K. L. S. of by to Rep. PubMed Scopus Google Scholar, S. A. S. M. C. et and PubMed Scopus Google by the of E3 ubiquitin to the of the proteins R. and molecular to 2017; PubMed Scopus Google Scholar). and to a L. J. Dong L. TiPARP nuclear to and Sci. S. A. PubMed Scopus Google that TiPARP and targets for proteasomal degradation and other nuclear transcriptional that is, and the by nuclear with the E3 ubiquitin ligase and several other E3 ubiquitin that AHR degradation occurs via the in the of the E3 ubiquitin ligase CUL4B as abolished AHR degradation in MEFCul4b-null cells the role for E3 ubiquitin ligase in AHR degradation. are to or reported E3 ubiquitin ligase is in activated AHR proteasomal degradation. also that TiPARP and CUL4B have in AHR transcriptional as AHR protein levels by the loss of CUL4B or CUL4B and TiPARP to enhanced TCDD of and and and are with that of AHR proteasomal degradation (10Pollenz R.S. The mechanism of AH receptor protein down-regulation (degradation) and its impact on AH receptor-mediated gene regulation.Chem. Biol. Interact. 2002; 141: 41-61Crossref PubMed Scopus (183) Google and TiPARP L. L. S. J.P. J. 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase is a and repressor of aryl hydrocarbon receptor Res. PubMed Scopus Google Scholar, L. S. L. J. J. hydrocarbon receptor repressor and TiPARP but also mechanisms to aryl hydrocarbon receptor J. Sci. PubMed Scopus Google led to AHR levels and AHR transcriptional be in the to study that the function of TiPARP can or the of TCDD and other environmental that the TiPARP identified that TiPARP can AHR activation known CUL4B have been identified also the that loss of CUL4B the of in control and cells that CUL4B by of AHR AHR ubiquitination, nuclear and degradation of the AHR to for as has been reported for other proteins that after by R. and molecular to 2017; PubMed Scopus Google Scholar, L. J. Dong L. TiPARP nuclear to and Sci. S. A. PubMed Scopus Google Scholar). AHR The that CUL4B has been reported to be in the nucleus J. and of the cullin E3 ligase proteins and PubMed Scopus Google Scholar, L. L. L. role of the CUL4B ubiquitin ligase in mouse Res. 22: PubMed Scopus Google and that et A. M. K. S. A. K. S. receptor is a E3 ubiquitin PubMed Scopus Google identified and the protein complex from nuclear the that the AHR is exported from the nucleus to the although is that the AHR can be degraded in the nucleus in the of a ligand Pollenz R.S. and of aryl hydrocarbon receptor and gene Pharmacol. 2002; PubMed Scopus Google Scholar), other from Pollenz Pollenz R.S. hydrocarbon receptor into the nucleus ligand binding is degraded via the nuclear Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, R.S. of the complex nuclear export and aryl hydrocarbon receptor-mediated gene Biol. PubMed Scopus Google and that the nuclear export TCDD-activated AHR degradation that the AHR degradation occurs by the in the cytoplasm after TCDD-activated AHR nuclear we that the complex and TiPARP have in AHR protein degradation and that and TiPARP have on AHR protein has a TiPARP on AHR and TiPARP is a factor for TCDD-activated AHR from the nucleus to the cytoplasm and proteasomal degradation. MEFCul4b-null cell line was from the CUL4B mouse in L. L. L. role of the CUL4B ubiquitin ligase in mouse Res. 22: PubMed Scopus Google in the of The WT MEF cell line was also from the control mouse in L. L. L. role of the CUL4B ubiquitin ligase in mouse Res. 22: PubMed Scopus Google Scholar). Cell in with and for the of compounds in the to activation of the AHR in control S. R. A. L. Rifkind A.B. tryptophan CYP1A in and in Sci. 2006; PubMed Scopus Google Scholar). and as TCDD in from in from mouse was by MEF cells in with and The cells for with TCDD or the in was for the of to of was with of and to The was for for and for The was in was in a of and and the of The for and are in the WT MEF or MEFCul4b-null cells cell of in the with TiPARP or in the after cells with TCDD or the after cells in for and or in for MEF cells in and for protein by the of protein from to on and to and as and Cell or mouse binding protein with by and to or levels WT MEF or MEFCul4b-null cells in Cell cell was with of of of protein and to control TiPARP gene the the from to in the of the mouse TiPARP gene was with the and after and with in to a cell with Cell for TiPARP by the WT and cells cell of in The cells with TCDD or cells with of or its control in the after with cells in for and to expression the in the and from MEF cells by the and the with the II was a of of cell and was of cells for The was while the was with The for the same the of the and nuclear and AHR protein in MEF cells by cells in on a cell of in with and The cells with or and by TCDD or cells in a of for and in in for with an AHR cells with two and with a with for two with and on an and a was as the nuclear of AHR S. of of the was by as a are in the and in the This The that have of with the of of for M. S. and A. B. R. M. S. C. and A. B. R. M. S. and A. B. R. M. S. and A. B. R. M. S. and A. B. R. and S. C. and A. B. R. S. S. and A. B. R. A. B. R. A. B. R. A. B. R. This was by the of of to A. B. R. and S. of and to The of is the of the and not the of the of

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