Biliverdin Reductase, a Novel Regulator for Induction of Activating Transcription Factor-2 and Heme Oxygenase-1

Abstract

Biliverdin IXα reductase (BVR) catalyzes reduction of the HO activity product, biliverdin, to bilirubin. hBVR is a serine/threonine kinase that contains a bZip domain. Presently, regulation of gene expression by hBVR was examined. 293A cells were infected with adenovirusdoxycycline (Ad-Dox)-inducible hBVR cDNA. High level expression of hBVR was determined at mRNA, protein, and activity levels 8 h after induction. Cell signal transduction microarray analysis of cells infected with expression or with the control Ad-inverted (INV)-hBVR vector identified ATF-2 among several up-regulated genes. ATF-2 is a bZip transcription factor for activation of cAMP response element (CRE) and a dimeric partner to c-jun in MAPK pathway that regulates the stress protein, HO-1, expression. Northern and Western blot analyses showed increases of ∼10-fold in ATF-2 mRNA and protein at 16 and 24 h after Dox addition. Ad-INV-hBVR did not effect ATF-2 expression. In hBVR-infected cells, levels of HO-1 mRNA and protein were increased. In vitro translated hBVR and nuclear extract containing hBVR in gel mobility-shift assay bound to AP-1 sites in the ATF-2 promoter region and to an oligonucleotide containing the CRE site. Both bindings could be competed out by excess unlabeled probe; in the presence of hBVR antibody, they displayed shifted bands. Co-transfection of hBVR with ATF-2 or c-jun promoters caused a severalfold increase in luciferase activity. hBVR modulation of ATF-2 and HO-1 expression suggests it has a potential role in regulation of AP-1 and cAMP-regulated genes and a role in cell signaling. We propose that increased expression of the protein can be used to alter the gene expression profile in the cell. Biliverdin IXα reductase (BVR) catalyzes reduction of the HO activity product, biliverdin, to bilirubin. hBVR is a serine/threonine kinase that contains a bZip domain. Presently, regulation of gene expression by hBVR was examined. 293A cells were infected with adenovirusdoxycycline (Ad-Dox)-inducible hBVR cDNA. High level expression of hBVR was determined at mRNA, protein, and activity levels 8 h after induction. Cell signal transduction microarray analysis of cells infected with expression or with the control Ad-inverted (INV)-hBVR vector identified ATF-2 among several up-regulated genes. ATF-2 is a bZip transcription factor for activation of cAMP response element (CRE) and a dimeric partner to c-jun in MAPK pathway that regulates the stress protein, HO-1, expression. Northern and Western blot analyses showed increases of ∼10-fold in ATF-2 mRNA and protein at 16 and 24 h after Dox addition. Ad-INV-hBVR did not effect ATF-2 expression. In hBVR-infected cells, levels of HO-1 mRNA and protein were increased. In vitro translated hBVR and nuclear extract containing hBVR in gel mobility-shift assay bound to AP-1 sites in the ATF-2 promoter region and to an oligonucleotide containing the CRE site. Both bindings could be competed out by excess unlabeled probe; in the presence of hBVR antibody, they displayed shifted bands. Co-transfection of hBVR with ATF-2 or c-jun promoters caused a severalfold increase in luciferase activity. hBVR modulation of ATF-2 and HO-1 expression suggests it has a potential role in regulation of AP-1 and cAMP-regulated genes and a role in cell signaling. We propose that increased expression of the protein can be used to alter the gene expression profile in the cell. The well known function of biliverdin IXα reductase (BVR) 1The abbreviations used are: BVR, biliverdin reductase; hBVR, human BVR; HO, heme oxygenase; AP-1, activating protein-1; ATF-2, activating transcription factor-2; Ad, adenovirus; Dox, doxycycline; CRE, cAMP response element; bZip, leucine zipper; MAPK, mitogen-activated protein kinase; INV, inverted; pfu, plaque-forming unit(s); CMV, cytomegalovirus; ELISA, enzyme-linked immunosorbent assay; EGFP, enhanced green fluorescent protein; TRE, Tet-responsive element. 1The abbreviations used are: BVR, biliverdin reductase; hBVR, human BVR; HO, heme oxygenase; AP-1, activating protein-1; ATF-2, activating transcription factor-2; Ad, adenovirus; Dox, doxycycline; CRE, cAMP response element; bZip, leucine zipper; MAPK, mitogen-activated protein kinase; INV, inverted; pfu, plaque-forming unit(s); CMV, cytomegalovirus; ELISA, enzyme-linked immunosorbent assay; EGFP, enhanced green fluorescent protein; TRE, Tet-responsive element. is catalysis of biliverdin reduction to bilirubin (1Singleton J.W. 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Full Text Full Text PDF PubMed Scopus Google cell the MAPK for and HO-1 is among genes expression can be up-regulated by activation of the MAPK The of HO-1 with an enhanced stress Alam J. M. H. M. Nat. Med. PubMed Scopus Google Scholar, R. R. R. Biol. Med. PubMed Scopus Google Scholar, D. J. Med. 2002; PubMed Scopus Google Scholar, P. Alam J. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, Exp. Biol. Med. 2003; 228: PubMed Scopus Google Scholar, K. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, M.D. Sci. 2003; PubMed Scopus Google and the product of HO biliverdin, has been to an role in the of to in M. Proc. Natl. Acad. Sci. U. S. A. 2002; PubMed Scopus Google Scholar). HO-1 stress response is by AP-1 to of J. D. J. Biol. Chem. 1992; 267: Full Text PDF PubMed Google Scholar). 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The was with and and the sites of vector The of hBVR was by it was used by S. of of the in the was by in The of containing the was the sites of vector The that and to with of the control of the promoter the in the were used for into vector to the and were an and with and and by to of the and were into 293A cells the The were cell by the to the The was determined by assay in with the of Cell and of hBVR into 293A cell human cell was for analysis and for protein were in containing and for was at a of of for and for was to be for of the of the cells were and used as h after the of the Dox was at a of was in as the were at in Northern was with an 293A cells infected or with or was by gel and The were for hBVR hBVR PubMed Scopus Google of S. R. Taguchi H. T. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google ATF-2, of the containing human ATF-2 of and human of human were with the system and were as T. Biol. 2003; PubMed Scopus Google Scholar). 293A cells infected with and or Ad-INV-hBVR and 24 h after with was used for microarray analysis by and the were with containing genes with signal transduction of the was with with system to signal to a signal were to genes and protein in genes expression were as the of after and the microarray analysis a was as a and is in the gene was as identified by microarray analysis by hBVR The in the the of the signal for genes in cells with or with was as and in the the genes. family ATF-2 cAMP element protein heat shock transcription factor protein; cell heat shock protein; factor H. H. of protein heat shock protein protein kinase H. and pathway protein kinase kinase in a Western infected as were by for at with and in of Cell was to and to BVR was BVR as the M.D. Trakshel G.M. Arch. Biochem. Biophys. 1993; 300: 320-326Crossref PubMed Scopus (68) Google Scholar) and as the The hBVR protein was by to or by enhanced system The was by and by ATF-2 was by and were the hBVR and protein of cell to cells was In to of cell extract were protein was by an by to the of BVR cells infected with or Ad-INV-hBVR were in containing and and 293A cells were used as a Cell were and The hBVR activity was in the at as R.K. Maines M.D. J. Biol. Chem. 1981; 256: 3956-3962Abstract Full Text PDF PubMed Google Scholar, Google Scholar, S. A. S. N. K. T. Biochem. J. PubMed Scopus Google Scholar). 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ATF-2 protein was in vitro translated a containing a ATF-2 as of The translated ATF-2 protein was used in the CRE was at to the of used for gel of of the of are with potential AP-1 sites as by The has a of with AP-1 the have a of and The of ATF-2 is in the of are The with potential AP-1 sites as by The has a of with AP-1 the have a of and The of ATF-2 is in in a of cells in was by with of the ATF-2 promoter to into vector of c-jun promoter to N. N. T. A. R. Biol. PubMed Scopus Google and in luciferase containing of promoter containing a AP-1 R. Biol. 1992; PubMed Scopus (90) Google Scholar) by and of of or containing hBVR of or of vector the h of cells were by The were by cell for at at and of were for luciferase by was by and luciferase were of the for BVR the potential of hBVR to alter gene expression in the a system by was used to an hBVR was with a and in with the gene vector The presence of and for of BVR expression and The was into the vector in control of vector the in the The was to in as a of the The the of the in the presence of to Tet-responsive element of the promoter of and transcription of the gene control of the for the of of and the of with or or with a of as of hBVR among In it was that Dox in a of the and of protein of and were also of biliverdin reductase and activity of 293A cells infected with hBVR expression were infected with hBVR or the cells were used as the Northern blot as the was out as 24 h after of was used in BVR activity was at with as the by the of of biliverdin to bilirubin H. Maines M.D. J. Biol. Chem. 1992; 267: 4023-4029Abstract Full Text PDF PubMed Google and expression of mRNA was determined by Northern blot analysis signal that to the of BVR mRNA and was 24 h after the of cells with the levels of hBVR mRNA were in cells, in cells infected with or in cells infected with The that the increase is not to activation of hBVR transcription by the increase in mRNA of BVR was by a increase in of biliverdin reduction The of hBVR expression was examined. in was a increase in protein a and b) and activity in 293A cells with of hBVR was at the an Western blot analysis or a and be that BVR was with in cells of cell extract was used for the cells showed level reductase activity; of Dox it was increased a as that of expression of BVR The activity was at 24 h after the Dox induction. to cells, cells infected with or infected with hBVR showed level reductase activity. of hBVR was green in hBVR in the cells as by the green of the BVR was to be a protein; the nuclear of the protein is with its function as a of gene expression. cells by of BVR in in an of ATF-2 the genes that were by BVR, was the 293A cells 24 h after with containing BVR or with and to gene analysis of cell genes. of genes were identified by the the genes with in signal are in the the of function is in the The genes are of signal transduction as pathway and pathway pathway and pathway and pathway pathway pathway pathway pathway and protein kinase pathway pathway and stress response pathway and into that hBVR is a potential transcription factor for AP-1 genes M. Maines M.D. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google and the of the of genes identified by microarray analysis AP-1 transcription could be by hBVR The ATF-2 contains potential AP-1 sites in its was for BVR in regulates ATF-2 mRNA and protein cells were infected with infected with the were used as The were at after and used for Northern blot analysis of ATF-2 mRNA and ATF-2 protein by Western blot in ATF-2 mRNA was in cells to the of the ATF-2 mRNA was increased with and levels were at 16 The signal for the control for was the of the with hBVR also in a increase of ATF-2 protein expression The increase was h after and at the The of ATF-2 is enhanced by T. PubMed Scopus Google Scholar). the of ATF-2 was also increased by of BVR in the cells, the protein was with to in an increase in the of ATF-2 is 16 h after with The suggests that hBVR ATF-2 it is not the increase in of ATF-2 is the of of hBVR with ATF-2 or modulation of that in ATF-2 levels were not cells were with the hBVR to the ATF-2 of hBVR in 293A cells in a increase in ATF-2 mRNA, hBVR with in the ATF-2 promoter We showed that hBVR to the AP-1 sites in the HO-1 promoter region M. Maines M.D. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). potential AP-1 sites were in the ATF-2 promoter containing the potential sites was the ATF-2 promoter by and in has a of with an AP-1 the have a of and AP-1 assay was out hBVR translated in vitro a protein and the ATF-2 promoter was with in in the gel a protein signal was the of unlabeled was used for in the of the was unlabeled at a excess of the was in the of was by the that hBVR to the in a the potential of as by the gel assay with in vitro translated hBVR, nuclear extract cells with at and 24 h after of hBVR expression was used for in the gel assay a increase in of in the of a In a shifted the of the AP-1 The that hBVR be among the that could effect ATF-2 BVR to of CRE, is the for dimeric ATF-2, the AP-1 by the presence of to that of AP-1 sites hBVR also to gel mobility-shift assay was with in vitro translated hBVR protein and containing CRE as in in of CRE oligonucleotide with translated hBVR protein a that was by the gel the of CRE unlabeled oligonucleotide assay was in the the of the gel was in the presence of unlabeled CRE In the presence of unlabeled at and in excess of the signal for was by and The control for the was in vitro translated in the an was was not with of CRE or CRE was the gel assay nuclear extract cells with at and 24 h after of hBVR expression a increase of and of to the in a that hBVR protein is of to CRE and that hBVR to to that as ATF-2, BVR of ATF-2 and were to the effect of hBVR expression ATF-2 promoter gene and c-jun promoter gene expression The to of ATF-2 promoter and to of c-jun a region that is of sites for AP-1 sites N. N. T. A. R. Biol. PubMed Scopus Google was in the vector containing luciferase and activity of the promoters was luciferase assay ATF-2 and c-jun promoters severalfold increase in luciferase activity. luciferase activity was in cells with or with luciferase vector and Co-transfection of the hBVR expression vector with ATF-2 or c-jun promoter caused an increase in luciferase activity. activity was to the promoter activity cells were with of hBVR with vector containing c-jun promoter at its in an promoter R. Biol. 1992; PubMed Scopus (90) Google did not luciferase activity. by Northern analysis and gel that BVR is of activating ATF-2 and c-jun HO-1 in The of increased expression of hBVR HO-1 was examined. studies BVR the presence of BVR is for HO-1 stress response M. Maines M.D. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google AP-1 ATF-2 a with with for AP-1 Presently, increased expression of BVR HO-1 expression. in HO-1 mRNA in cells was increased at h after of Dox The increase in HO-1 mRNA did not in increase in HO-1 protein as by ELISA, was with an increase in HO-1 mRNA The of HO-1 in control cells was of cell proteins with that of cells of the control We the features of the presence of the bZip in the of hBVR, with kinase activity of the reductase and its nuclear in response to stress and (17Salim M. Brown B.A. Maines M.D. J. Biol. Chem. 2001; 276: 10929-10934Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, M.D. Huang T.J. N. J. Exp. 2001; Google Scholar, M. Maines M.D. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google with of a protein that could effect gene was by that hBVR could to a HO-1 promoter containing AP-1 sites and J. D. J. Biol. 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CRE the AP-1 by of in vitro translated hBVR and nuclear extract of cells hBVR to the AP-1 and CRE, not that hBVR regulates ATF-2 or HO-1 with the of mRNA and protein analyses a role for hBVR in regulation of ATF-2 and HO-1 gene expression a of the for expression. levels of ATF-2 in cells hBVR a of ATF-2 is a transcription factor that of is an is not P. M. Biophys. PubMed Scopus Google Scholar, T. PubMed Scopus Google Scholar). and ATF-2, BVR, are and in or The of the dimeric partner for In the of ATF-2, it can a with its levels are it with the partner of The to the AP-1 sites the of ATF-2, CRE response T. PubMed Scopus Google Scholar, H. K. K. Scopus (11) Google Scholar, K. S. J. 2002; PubMed Scopus Google Scholar). The is the Google Scholar). not ATF-2 with in among CRE sites H. R. A. A.J. P. P. J. 1993; PubMed Scopus Google Scholar) also gene regulation activity of the dimeric The of hBVR to ATF-2, is to the profile of gene expression in the cell. In the of with to a of AP-1 the in a of in the cell. AP-1 sites are in promoters of a genes that control transcription of and P. M. R. B. P. M. 1987; Full Text PDF PubMed Scopus Google Scholar). AP-1 is activated by and ATF-2, in to the dimeric of an role in of c-jun gene expression and its by ATF-2 also with D. T. 1993; Full Text PDF PubMed Scopus Google Scholar). is a of a of as and D. T. 1993; Full Text PDF PubMed Scopus Google Scholar, P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is to that to of genes for of and family of be by an increase in ATF-2 in the cell. by hBVR of ATF-2, be by activity is is a of the that to as and D. T. 1993; Full Text PDF PubMed Scopus Google Scholar, P. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google the of BVR to increase ATF-2 gene expression be of potential in to is to a an increase in ATF-2 expression and increase in that of HO-1 expression. of the MAPK pathway and is a for the of HO-1 is also to gene activation by cAMP N. K. R.K. Am. J. Physiol. 1997; Google Scholar, L. J. Physiol. PubMed Scopus Google Scholar, J. D. D. B.A. S. J. Biol. Chem. Full Text PDF PubMed Google Scholar). it is to that of ATF-2 has a effect HO-1 expression. the be out that the of HO-1 gene expression in cells hBVR is of In at the can be the of the product, biliverdin, by hBVR in a reductase and the activation of genes that control HO-1 gene for that of in c-jun is among the of genes identified by microarray analyses to be up-regulated in cells infected with that or a of the are in increased expression of HO-1 is a the of that are by HO activity and of heme catalysis Alam J. M. H. M. Nat. Med. PubMed Scopus Google Scholar, R. R. R. Biol. Med. PubMed Scopus Google Scholar, D. J. Med. 2002; PubMed Scopus Google Scholar, P. Alam J. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, Exp. Biol. Med. 2003; 228: PubMed Scopus Google Scholar, K. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, M.D. Sci. 2003; PubMed Scopus Google the that hBVR a role in regulation of HO-1 expression could be as a for a of modulation of hBVR expression in the cell in regulation of genes that are in and We are to for of the and for of the for human ATF-2 and S. of for and of for with c-jun promoter used for luciferase and of for the ATF-2 expression