The phosphatidylinositol 3-kinase (PI3K)/Akt pathway elicits a survival signal against multiple apoptotic insults. In addition, phase II enzymes such as heme oxygenase-1 (HO-1) protect cells against diverse toxins and oxidative stress. In this work, we describe a link between these defense systems at the level of transcriptional regulation of the antioxidant enzyme HO-1. The herb-derived phenol carnosol induced HO-1 expression at both mRNA and protein levels. Luciferase reporter assays indicated that carnosol targeted the mouse ho1 promoter at two enhancer regions comprising the antioxidant response elements (AREs). Moreover, carnosol increased the nuclear levels of Nrf2, a transcription factor governing AREs. Electrophoretic mobility shift assays and luciferase reporter assays with a dominant-negative Nrf2 mutant indicated that carnosol increased the binding of Nrf2 to ARE and induced Nrf2-dependent activation of the ho1 promoter. While investigating the signaling pathways responsible for HO-1 induction, we observed that carnosol activated the ERK, p38, and JNK pathways as well as the survival pathway driven by PI3K. Inhibition of PI3K reduced the increase in Nrf2 protein levels and activation of the ho1 promoter. Expression of active PI3K-CAAX (where A is aliphatic amino acid) was sufficient to activate AREs. The use of dominant-negative mutants of protein kinase Cζ and Akt1, two kinases downstream from PI3K, demonstrated a requirement for active Akt1, but not protein kinase Cζ. Moreover, the long-term antioxidant effect of carnosol was partially blocked by PI3K or HO-1 inhibitors, further demonstrating that carnosol attenuates oxidative stress through a pathway that involves PI3K and HO-1. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway elicits a survival signal against multiple apoptotic insults. In addition, phase II enzymes such as heme oxygenase-1 (HO-1) protect cells against diverse toxins and oxidative stress. In this work, we describe a link between these defense systems at the level of transcriptional regulation of the antioxidant enzyme HO-1. The herb-derived phenol carnosol induced HO-1 expression at both mRNA and protein levels. Luciferase reporter assays indicated that carnosol targeted the mouse ho1 promoter at two enhancer regions comprising the antioxidant response elements (AREs). Moreover, carnosol increased the nuclear levels of Nrf2, a transcription factor governing AREs. Electrophoretic mobility shift assays and luciferase reporter assays with a dominant-negative Nrf2 mutant indicated that carnosol increased the binding of Nrf2 to ARE and induced Nrf2-dependent activation of the ho1 promoter. While investigating the signaling pathways responsible for HO-1 induction, we observed that carnosol activated the ERK, p38, and JNK pathways as well as the survival pathway driven by PI3K. Inhibition of PI3K reduced the increase in Nrf2 protein levels and activation of the ho1 promoter. Expression of active PI3K-CAAX (where A is aliphatic amino acid) was sufficient to activate AREs. The use of dominant-negative mutants of protein kinase Cζ and Akt1, two kinases downstream from PI3K, demonstrated a requirement for active Akt1, but not protein kinase Cζ. Moreover, the long-term antioxidant effect of carnosol was partially blocked by PI3K or HO-1 inhibitors, further demonstrating that carnosol attenuates oxidative stress through a pathway that involves PI3K and HO-1. High levels of reactive oxygen species cause damage to cells and are involved in several human pathologies, including neurodegenerative disorders and cancer (1Klein J.A. Ackerman S.L. J. Clin. 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Motterlini R. Mol. Pharmacol. 2002; 61: 554-561Crossref PubMed Scopus (294) Google Scholar). Many reports have demonstrated the potent antioxidant activity of the heme-derived metabolites generated by HO-1 catalysis (biliverdin and bilirubin) and the of carbon monoxide and nerve cells K. K. M.D. J. 2000; PubMed Scopus Google Scholar, F. A. G. A. Abraham N.G. Biol. Med. 2003; PubMed Scopus Google Scholar, M.D. Toxicol. Sci. 2003; PubMed Scopus Google Scholar, J. Y. C. E. J. 2003; PubMed Scopus Google Scholar). Moreover, both S. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google and a human of HO-1 Y. L. S. T. Y. A. S. 2000; PubMed Scopus Google exhibit a of iron to and oxidative damage and Therefore, is that of HO-1 expression response that to oxidative The signaling used to activate transcription of phase II such as HO-1 are have the activation of the mitogen-activated protein kinases to growth and stress In the pathways are by kinase to activation of extracellular signal-regulated kinase c-Jun N-terminal kinase and a R. 2002; PubMed Scopus Google Scholar). pathways to involved to in the of HO-1 expression in response to diverse stimuli. in to HO-1 expression activation of and the JNK but not the pathway T. A. S. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). the other HO-1 expression the and pathways in cells Y. J. Biochem. 2000; PubMed Scopus Google Scholar). in the HO-1 through JNK and A. S. I. Katz N. S. Biol. Med. 2003; Scopus Google Scholar). curcumin HO-1 through the pathway in cells E. M. Gong P. Killeen E. Green C.J. Foresti R. J. Motterlini R. 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PubMed Scopus Google Scholar, N. A.M. 2003; PubMed Scopus Google Scholar). a of to oxidative stress of phase II These regions are stress response elements or antioxidant response elements and are regulated by the transcription factor Nrf2 T. Rev. Pharmacol. Toxicol. 2002; PubMed Scopus Google Scholar). Nrf2 is a member of the family of transcription P. K. I. A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). Nrf2 is in the by binding to protein K. N. Y. T. K. M. 1999; PubMed Scopus Google Scholar). including oxidative to the of this Nrf2 for to the and with transcription such as and family M. 2001; PubMed Scopus Google Scholar). The by which Nrf2 is from the but involves and of Nrf2 protein T. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, T. Yang J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google which a of and is the pathway T. Yang J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, D. Killeen E. Naquin R. S. J. J. Biol. Chem. 2002; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, M. K. M. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). In this we the effect of carnosol expression of the antioxidant enzyme HO-1, and we the signaling pathways to HO-1 that carnosol HO-1 expression by Nrf2 protein levels in a Therefore, in to its antioxidant carnosol the survival pathway and expression of HO-1. with and that not in cells (13Salinas M. Diaz R. Abraham N.G. Ruiz de Galarreta C.M. Cuadrado A. J. Biol. Chem. 2003; 278: 13898-13904Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar, D. M. R. E. M. Cuadrado A. J. 2001; PubMed Scopus Google Scholar). luciferase of cells and cells and in with and in the expression J. C. Stewart D. Gong P. C. S. Choi A.M. J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google D. M. R. E. M. Cuadrado A. J. 2001; PubMed Scopus Google by J. de and was used to the growth factor and carnosol from and and from These in and used at a of of mRNA by and was of from the for at of in the of of of was in of and of and of for HO-1 and that of to the the was and for at of was for the of that of HO-1 mRNA levels in cells not for and for HO-1, a of at at and at The by and with was with of as in and and and and the and in Green was in as for for at for and for HO-1 expression was in and was to expression levels. of cells with and by at for The was in of and The was at for and the nuclear was in of and at for in of and and for at a was by at for at of the was by and to and The of the was used for electrophoretic mobility shift was with the protein used as the Nrf2 was The was by at a of in and at for The was to with a of in a to in The was with kinase of and of The a The binding of nuclear in and in a of or was as and the was for at was to the and to at at a in the was and of by and to with the and and of de and and used to the proteins of by was used to reactive oxygen species with the 2′,7′-dichlorodihydrofluorescein The which the and is and to to zinc-protoporphyrin indicated for and from the with and of cells for was used to between A was luciferase and at or The in to the of at with representative from that two to Expression of the that a diterpene derived from the herb rosemary, the expression of the antioxidant enzyme HO-1. cells for in with and or with and both cells a as by of and at the of these not and D. M. R. E. M. Cuadrado A. J. 2001; PubMed Scopus Google Scholar). with carnosol for or with of of and for the of HO-1 In with a R. W. J. 2003; PubMed Scopus Google cells in a in HO-1 protein levels with cells in carnosol induced a increase in HO-1 protein levels that was in cells to further the effect of carnosol of HO-1 cells in for and for with carnosol concentrations from to indicated that carnosol induced a increase in HO-1 mRNA at Moreover, as in also a increase in HO-1 mRNA levels. increase was not as as that with and and to mRNA levels in the was to increase the linear in the In addition, carnosol also a increase in HO-1 protein levels to the other isozyme in these cells with these carnosol also induced a increase in HO-1 mRNA levels that was as as and was by a increase in HO-1 protein levels at and in other of human and mouse not Therefore, these that carnosol expression of the HO-1 HO-1 through the mouse ho1 promoter two that of regulation by this cells with luciferase expression the mouse promoter or mutant the or ARE or both in for and with carnosol for in of ARE or in and in carnosol induction, of both the response to Therefore, these that carnosol HO-1 expression through both AREs. the of the Nrf2 transcription have to with AREs. that of HO-1 expression by several de protein K. M.D. Cell. Mol. Biol. (Noisy-le-Grand). 2000; 46: Google Scholar, N. L. V. A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google we the that this Nrf2, a transcription factor with a T. Yang J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, D. Killeen E. Naquin R. S. J. J. Biol. Chem. 2002; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, M. K. M. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google that AREs. cells in for and for with the carnosol concentrations indicated in a cells also with the In with T. Yang J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, D. Killeen E. Naquin R. S. J. J. Biol. Chem. 2002; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, M. K. M. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google of with in a large of Nrf2 protein in the of carnosol increased Nrf2 levels in a with the effect at in we the of Nrf2 in the of in the of Nrf2 protein was in the of carnosol and increased for at the with the and carnosol not increase Nrf2 levels with that carnosol degradation of Nrf2 the we the nuclear levels of Nrf2 in both and carnosol induced a of Nrf2 in the the levels of the transcription factor Moreover, we the increase in Nrf2 in the was sufficient to binding of protein this transcription factor to the ARE to the mouse ho1 promoter. with nuclear from cells to carnosol or in of the several was increased in with carnosol or Moreover, the was in the of the of this the of Nrf2 in the these that carnosol both and nuclear protein levels of Nrf2, in increased binding to the ARE promoter of HO-1. the of Nrf2 binding to the ho1 ARE, cells with and expression for dominant-negative mutants of Nrf2 or of its in the activation of the ho1 promoter was in the of dominant-negative Nrf2 or or both These further that Nrf2 the activation of the ho1 promoter. the and the the signaling pathways used by carnosol to HO-1 we the effect of this the to activation of ERK, and JNK and the survival pathway by the PI3K and The activation of these pathways was with that the active and of ERK, p38, JNK, and with carnosol for the indicated and with in carnosol activated the as well as the pathway with activation of was observed of activation of JNK, and at Moreover, activation was Therefore, we which of these pathways involved in the for HO-1 in for with of pathway and and with carnosol for The of these was in cells with for transcription and not in HO-1 protein levels increased with as Inhibition of the and JNK pathways or effect HO-1 protein that these are not for HO-1 by of both PI3K to a pathways reduced the of carnosol to increase HO-1 protein of and PI3K of HO-1 by with with used for cells in for and with or for to carnosol for carnosol luciferase activity in the mouse ho1 promoter in the of the and PI3K cells with and cells to in the of the and with carnosol for and for luciferase and further these we the effect of carnosol the of the mouse ho1 cells with expression for for and cells with the and PI3K for and with carnosol for in carnosol increased luciferase with the that HO-1 Moreover, the of this promoter was reduced in the of the and PI3K and in the of the and JNK Therefore, these the mouse promoter with the of the HO-1 protein and that carnosol PI3K to a kinases to HO-1 expression in other have the of in activation of HO-1 in the of E. M. Gong P. Killeen E. Green C.J. Foresti R. J. Motterlini R. Biochem. J. 2003; PubMed Scopus Google we the of PI3K. in with several concentrations of the PI3K and to carnosol for a for the and of the we the activation of the PI3K downstream of carnosol with the concentrations in the the activation of and also at the increase in HO-1 and Nrf2 protein levels. Therefore, these that PI3K is to HO-1 expression and that the Nrf2 transcription factor may at in this we PI3K is sufficient to activate the ho1 promoter and the of in such a cells with expression for active PI3K A is aliphatic amino and a luciferase expression or in active PI3K was sufficient to the activity of the ho1 promoter. this activation was in the mutants the or and was reduced in the mutant both In addition, we the requirement of Nrf2 for activation of the ho1 promoter. cells with and PI3K-CAAX with the expression for dominant-negative Nrf2 and In several the effect of PI3K-CAAX the ho1 promoter was in this of with the by of two or as in dominant-negative Nrf2 and or in blocked activation of the ho1 promoter. These that PI3K is sufficient to activate the ho1 promoter through the in Nrf2-dependent also the of kinases regulated by PI3K to the of HO-1. cells with the expression and dominant-negative of and protein kinase Cζ two well of PI3K. of these proteins was by with in with dominant-negative not have a effect the response to as in dominant-negative blocked the of HO-1. Moreover, of both expression carnosol to the as dominant-negative not These that is responsible for at of the of HO-1. Moreover, as in cells with active PI3K and increased HO-1 protein further that the is sufficient to HO-1 we carnosol attenuates oxidative stress through the of HO-1 expression and the of the PI3K pathway to such cells in for for at with H2DCFDA, a that cells and is and in the to the green A. J.A. 1999; PubMed Scopus Google Scholar). cells with or carnosol for and to for by in and concentrations of carnosol the of the the of Moreover, as in carnosol the of by concentrations from to the of the carnosol was to a effect these the antioxidant of this in with other K. Pharmacol. 2001; Google Scholar). we the long-term effect of carnosol a a with the of HO-1 expression through the pathway in this The antioxidant effect of carnosol was in the of the HO-1 and the PI3K cells in for with or as indicated in and and with carnosol for or cells with for and by in not the antioxidant effect of carnosol a partially not blocked the long-term antioxidant effect of carnosol a as in of PI3K by not the antioxidant effect of carnosol a but partially reduced its antioxidant effect a These that of HO-1 by carnosol through the PI3K pathway is to at of its long-term antioxidant In this we have the of the survival pathway in the of HO-1, a phase II in response to the herb-derived diterpene that carnosol HO-1 expression by the ARE in the mouse ho1 promoter. The regulation of by carnosol was at in through increase in Nrf2 protein levels in a and this is the the activation of the pathway and its to the of phase II enzymes by with the regulation of phase II expression have the of the the ERK, p38, and JNK pathways are activated by they not in the of HO-1 in and JNK are for HO-1 of the response to The of in ARE activation in with dominant-negative mutants of JNK not prevent of the mouse ho1 promoter J. C. Stewart D. Gong P. C. S. Choi A.M. J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). in the glutathione and a of ho1 expression T. A. S. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, T. M. S. S. T. J. Pharmacol. 1998; Google Scholar). E. M. Gong P. Killeen E. Green C.J. Foresti R. J. Motterlini R. Biochem. J. 2003; PubMed Scopus Google the effect of curcumin of HO-1 expression by of the in a and binding of Nrf2 to the AREs. a activation of the ho1 promoter in the R.J. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus (219) Google but of effect and HO-1 mRNA in cells Y. K. R. S. J. Biochem. 1998; PubMed Scopus Google Scholar). are with the requirement of for activation of the ho1 promoter by carnosol a of reduced Nrf2 protein levels not and HO-1 protein levels and promoter activity in response to the pathway is for HO-1 in and in cells with T. A. S. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google but is in the response in cells R.J. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus (219) Google Scholar). for these may from the diverse and of the signaling pathways activated by in In this is to that carnosol to HO-1 at the the that this the activation of the pathways not therefore that may not the of the and but also the of these that carnosol increased the levels of the Nrf2 transcription factor in the and its binding to the AREs. The to nuclear of Nrf2 are but include the release from in the the of this transcription factor is T. Yang J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, D. Killeen E. Naquin R. S. J. J. Biol. Chem. 2002; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, M. K. M. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google these the of Nrf2 that carnosol increased the levels of Nrf2, as the that this Nrf2 The increase in Nrf2 protein levels induced by carnosol was partially the activation of PI3K concentrations that PI3K and the and activation of the of Nrf2 of PI3K not prevent the increase in Nrf2 and HO-1 protein that other and other are also involved in carnosol signaling to Nrf2 and HO-1. active PI3K was sufficient to activate the ho1 promoter through and expression of active PI3K or cells with increased HO-1 levels. In for the downstream kinases that responsible for the increased Nrf2 protein we the effect of A dominant-negative of this kinase a in the activation of the ho1 a for this in HO-1 transcriptional a by S. M. A. S. T. Am. J. Physiol. 2003; PubMed Scopus Google indicated that member of the Nrf2 at to its release from and nuclear the of is to a of in the regulation of Nrf2 or to with other such as to the other a dominant-negative mutant of the activation of the ho1 promoter. to of Nrf2 or by these proteins not have a for Nrf2 is regulated at the level of we that the involved in its for In at two Proc. Natl. Acad. Sci. U. S. A. 2001; 98: PubMed Scopus Google and S. D. N. A. J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google have to of the activation of by carnosol was a that by Nrf2 protein levels increased Therefore, activation of in of that Nrf2, in increased protein levels. of the in its to a increase in Nrf2 protein levels. the activation of activate transcription of proteins that to increased Nrf2 protein levels. exhibit antioxidant properties to Michael acceptor we have observed the antioxidant of carnosol a with this the effect of as as as by the in the of to its green for this of the PI3K pathway to activation of and of HO-1 expression the long-term not antioxidant function of therefore the of this pathway for carnosol in antioxidant a of of the antioxidant effect of carnosol was to of PI3K and HO-1 at is with the at this is carnosol to its antioxidant In the PI3K and HO-1 to levels to observed at we the that carnosol also other antioxidant systems that not to the and that also to the long-term antioxidant properties of this In from mouse cells that carnosol also the expression of and glutathione not A of this is that activation of the pathway by this to in Nrf2 and cells from oxidative stress and as a in such as and diseases that with oxidative for