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Cytochrome P450 2C9-induced Endothelial Cell Proliferation Involves Induction of Mitogen-activated Protein (MAP) Kinase Phosphatase-1, Inhibition of the c-Jun N-terminal Kinase, and Up-regulation of Cyclin D1*

  • Michael Potente
    Affiliations
    Institut für Kardiovaskuläre Physiologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
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  • U. Ruth Michaelis
    Affiliations
    Institut für Kardiovaskuläre Physiologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
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  • Beate Fisslthaler
    Affiliations
    Institut für Kardiovaskuläre Physiologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
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  • Rudi Busse
    Affiliations
    Institut für Kardiovaskuläre Physiologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
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  • Ingrid Fleming
    Correspondence
    To whom correspondence should be addressed. Tel.: 49-69-6301-6972; Fax: 49-69-6301-7668
    Affiliations
    Institut für Kardiovaskuläre Physiologie, Klinikum der Johann Wolfgang Goethe-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany
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  • Author Footnotes
    * This work was supported by Grant FI 830/1-1 from the Deutsche Forschungsgemeinschaft and by grants from the Heinrich and Fritz Riese-Stiftung and Institut de Recherches Internationales Servier.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Open AccessPublished:February 26, 2002DOI:https://doi.org/10.1074/jbc.M110806200
      Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) are important modulators of endothelial cell homeostasis. We investigated the signaling pathway linking the activation of CYP 2C9 to enhanced endothelial cell proliferation. Overexpression of CYP 2C9 in cultured human endothelial cells markedly increased proliferation. This effect was paralleled by an up-regulation of the G1 phase regulatory protein, cyclin D1. The specific CYP 2C9 inhibitor, sulfaphenazole, prevented both the enhanced cell proliferation and up-regulation of cyclin D1. CYP 2C9 overexpression also decreased the activity of the c-Jun N-terminal kinase (JNK). Coexpression of wild type JNK with CYP 2C9 attenuated the CYP 2C9-induced increase in cyclin D1 expression and abolished the CYP 2C9-induced proliferation response. In contrast, cotransfecting dominant negative JNK with CYP 2C9 restored the CYP 2C9-mediated up-regulation of cyclin D1 and proliferation. The inactivation of JNK is linked to its dephosphorylation by dual specificity mitogen-activated protein (MAP) kinase phosphatases (MKPs). Overexpression of CYP 2C9 significantly increased the expression of MKP-1, as did incubation with 11,12-EET. These data demonstrate that the mitogenic effect of CYP 2C9 is due to the generation of EETs, which promote the MKP-1-mediated dephosphorylation and inactivation of JNK, effects ultimately culminating in the expression of cyclin D1 and endothelial cell proliferation.
      CYP
      cytochrome P450
      EET
      epoxyeicosatrienoic acid
      MAP
      mitogen-activated protein
      MKP
      MAP kinase phosphatase
      JNK
      c-Jun N-terminal kinase
      ERK
      extracellular signal-regulated kinase
      BrdUrd
      bromodeoxyuridine
      ROS
      reactive oxygen species
      HUVEC
      human umbilical vein endothelial cells
      GST
      glutathione S-transferase
      CDK
      cyclin-dependent kinase
      Cytochrome P450 (CYP)1epoxygenases catalyze the epoxidation of arachidonic acid into a series of regio- and stereospecific epoxyeicosatrienoic acids (5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET) and play a crucial role in the regulation of vascular homeostasis (for a review, see Ref.
      • Fleming I.
      ). Initially, CYP-derived EETs were described to hyperpolarize and relax vascular smooth muscle cells as a consequence of the activation of large conductance Ca2+-dependent K+channels (BKCa+) (
      • Campbell W.B.
      • Gebremedhin D.
      • Pratt P.F.
      • Harder D.R.
      ,
      • Li P.L.
      • Zou A.P.
      • Campbell W.B.
      ,
      • Campbell W.B.
      • Falck J.R.
      • Gauthier K.
      ). However, several more recently reported cellular actions of EETs cannot be attributed to the activation of BKCa+, suggesting that EETs are more than just vasodilators. Indeed, EETs are reported to stimulate the ADP-ribosylation of G-proteins (
      • Li P.L.
      • Campbell W.B.
      ) as well as activate intracellular protein kinases including tyrosine kinases, the extracellular signal-regulated kinase 1 and 2 (ERK1/2), the p38 mitogen-activated protein (MAP) kinase, and protein kinase B (protein kinase B/Akt) (
      • Hoebel B.G.
      • Graier W.F.
      ,
      • Fleming I.
      • Fisslthaler B.
      • Michaelis U.R.
      • Kiss L.
      • Popp R.
      • Busse R.
      ,
      • Chen J.K.
      • Capdevila J.
      • Harris R.C.
      ). 11,12-EET has also been shown to exert anti-inflammatory effects by inhibiting the activation of the transcription factor NF-κB and decreasing the cytokine-induced expression of vascular cell adhesion molecule-1 (
      • Node K.
      • Huo Y.
      • Ruan X.
      • Yang B.
      • Spiecker M.
      • Ley K.
      • Zeldin D.C.
      • Liao J.K.
      ).
      CYP epoxygenases of the 2B, 2J, and 2C families are reported to be expressed in cultured and native endothelial cells (
      • Node K.
      • Huo Y.
      • Ruan X.
      • Yang B.
      • Spiecker M.
      • Ley K.
      • Zeldin D.C.
      • Liao J.K.
      ,
      • Lin J.H.C.
      • Kobari Y.
      • Zhu Y.
      • Stemerman M.B.
      • Pritchard Jr., K.A.
      ,
      • Fisslthaler B.
      • Popp R.
      • Kiss L.
      • Potente M.
      • Harder D.R.
      • Fleming I.
      • Busse R.
      ,
      • Fisslthaler B.
      • Hinsch N.
      • Chataigneau T.
      • Popp R.
      • Kiss L.
      • Busse R.
      • Fleming I.
      ); however, whereas expression of CYP 2J appears to be constitutive, stimuli such as pulsatile stretch or Ca2+ antagonists markedly enhance the expression of CYP 2C (
      • Fisslthaler B.
      • Popp R.
      • Kiss L.
      • Potente M.
      • Harder D.R.
      • Fleming I.
      • Busse R.
      ,
      • Fisslthaler B.
      • Hinsch N.
      • Chataigneau T.
      • Popp R.
      • Kiss L.
      • Busse R.
      • Fleming I.
      ,
      • Fisslthaler B.
      • Popp R.
      • Michaelis U.R.
      • Kiss L.
      • Fleming I.
      • Busse R.
      ). The resulting CYP 2C-induced changes in vascular function/homeostasis cannot only be attributed to the synthesis of EETs because this enzyme also generates biologically relevant amounts of reactive oxygen species (ROS) (
      • Fleming I.
      • Michaelis U.R.
      • Bredenkotter D.
      • Fisslthaler B.
      • Dehghani F.
      • Brandes R.P.
      • Busse R.
      ).
      We have reported previously that EETs activate MAP kinases and enhance endothelial cell growth (
      • Fleming I.
      • Fisslthaler B.
      • Michaelis U.R.
      • Kiss L.
      • Popp R.
      • Busse R.
      ). Therefore, the aim of the present investigation was to determine the cellular events linking CYP 2C with endothelial cell proliferation. We report here that the mitogenic effect of CYP 2C9 can be attributed to the generation of EETs, induction of MAP kinase phosphatase-1 (MKP-1), and inhibition of c-Jun N-terminal kinase (JNK) activity, effects ultimately culminating in the increased expression of cyclin D1 and endothelial cell proliferation.

      DISCUSSION

      We have demonstrated previously that the CYP 2C9 product, 11,12-EET, activates multiple signal transduction pathways in native and cultured endothelial cells and that overexpression of a CYP 2C epoxygenase enhances endothelial cell numbers (
      • Fleming I.
      • Fisslthaler B.
      • Michaelis U.R.
      • Kiss L.
      • Popp R.
      • Busse R.
      ). Therefore, we set out to elucidate the intracellular signal transduction cascade linking enhanced CYP expression and EET production with proliferation. The results of the present investigation demonstrate that the overexpression of CYP 2C9 in human endothelial cells stimulates cell proliferation by targeting the expression of the cell cycle regulatory protein, cyclin D1. The overexpression of CYP 2C9 increased the generation of EETs, which enhanced the expression of the immediate early gene product MKP-1. An MKP-1-mediated reduction in JNK activity resulted in an enhanced expression of cyclin D1, which mediated the proliferative effect of CYP 2C9 overexpression in endothelial cells.
      Progression through the mammalian cell cycle requires the activation of CDKs by their association with the cyclin proteins that are regulatory subunits. Different CDK-cyclin holoenzymes are activated at specific phases of the cell cycle, and active CDK-cyclin complexes phosphorylate the retinoblastoma gene product (pRb) and the related pocket proteins p107 and p130 from mid-G1 to mitosis. As a consequence of Rb hyperphosphorylation, the association between Rb and the transcription factor E2F is disrupted, facilitating the transcription of a bank of genes essential for DNA synthesis and S phase progression (
      • Ekholm S.V.
      • Reed S.I.
      ). We concentrated on the CYP 2C9-induced alterations in cyclin D1 expression as this relatively labile cyclin provides a link between mitogenic cues and the cell cycle machinery.
      Numerous pathways have been reported to regulate the expression of cyclin D1, but the MAP kinase family is generally assumed to play a crucial role in this process (
      • Cook S.J.
      • Balmanno K.
      • Garner A.
      • Millar T.
      • Taverner C.
      • Todd D.
      ). Depending on the cell type investigated, proliferative stimuli have been linked to the activation as well as the inactivation of ERK1/2, JNK, and the p38 MAP kinase (
      • Wilkinson M.G.
      • Millar J.B.
      ). In the present investigation, we observed that the phosphorylation and thus presumably the activation of the p38 MAP kinase was enhanced in CYP 2C9-overexpressing endothelial cells, whereas the activity of JNK was attenuated, and the phosphorylation of ERK1/2 was unaffected. Of the MAP kinases affected by CYP 2C9, a link between kinase activity and cyclin D1 expression could only be made for JNK, and a decrease in JNK activity was associated with an increase in cyclin D1 expression. Moreover, coexpression of CYP 2C9 and JNK prevented the CYP 2C9-induced induction of cyclin D1 expression as well as the CYP 2C9-induced increase in endothelial cell proliferation. Cyclin D1 expression and proliferation were, however, enhanced in endothelial cells, which overexpressed both CYP 2C9 and a dominant negative JNK mutant. Overexpressing CYP 2C9 together with either a wild type or dominant negative p38 MAP kinase did not affect cyclin D1 levels.
      The JNK/stress-activated protein kinase pathway is activated by numerous cellular stresses, and although it has been implicated in mediating apoptosis and growth factor signaling, its role in endothelial cell growth is unclear. The limited number of studies that specifically address the role of JNK in endothelial cell proliferation has, however, indicated that in vascular endothelial growth factor-treated and integrin-activated endothelial cells, the activation rather than the inactivation of JNK is associated with an increase in cyclin D1 expression, as well as endothelial cell proliferation and migration (
      • Pedram A.
      • Razandi M.
      • Levin E.R.
      ,
      • Oktay M.
      • Wary K.K.
      • Dans M.
      • Birge R.B.
      • Giancotti F.G.
      ,
      • Pedram A.
      • Razandi M.
      • Levin E.R.
      ). It is, however, more than likely that JNK activity is differentially regulated by different proliferative stimuli as, for example, insulin-stimulated cell proliferation and survival is reported to involve the phosphatidylinositol 3-kinase-mediated inhibition of JNK activity (
      • Desbois-Mouthon C.
      • Cadoret A.
      • Blivet-Van Eggelpoel M.J.
      • Bertrand F.
      • Caron M.
      • Atfi A.
      • Cherqui G.
      • Capeau J.
      ). Although the precise molecular steps between CYP-dependent JNK inactivation and cyclin D1 up-regulation remain to be identified, our findings indicate a novel role for JNK in the control of cyclin D1 expression in endothelial cells.
      To determine how CYP 2C9 attenuates the activity of JNK, we assessed the effects of CYP overexpression on the expression of MKP-1, a dual specificity protein phosphatase that is reported to exhibit a certain specificity/preference for JNK-1 (
      • Hirsch D.D.
      • Stork P.J.S.
      ,
      • Hofken T.
      • Keller N.
      • Fleischer F.
      • Goke B.
      • Wagner A.C.
      ). CYP 2C9 overexpression resulted in the induction of MKP-1 with a time course that paralleled the decrease in JNK activity and the increase in cyclin D1 expression.
      CYP 2C9 does not only generate EETs in endothelial cells, and this enzyme, like other CYP epoxygenases, generates ROS in amounts sufficient to affect intracellular signaling (
      • Fleming I.
      • Michaelis U.R.
      • Bredenkotter D.
      • Fisslthaler B.
      • Dehghani F.
      • Brandes R.P.
      • Busse R.
      ). Because ROS, such as superoxide anions and hydrogen peroxide (H2O2), have also been reported to affect MKP expression, MAP kinase activity, and cell proliferation (
      • Ruiz-Gines J.A.
      • Lopez-Ongil S.
      • Gonzalez-Rubio M.
      • Gonzalez-Santiago L.
      • Rodriguez-Puyol M.
      • Rodriguez-Puyol D.
      ,
      • Tournier C.
      • Thomas G.
      • Pierre J.
      • Jacquemin C.
      • Pierre M.
      • Saunier B.
      ,
      • Baas A.S.
      • Berk B.C.
      ,
      • Irani K.
      ), we determined whether or not the effects of CYP 2C9 overexpression could be mimicked by incubating endothelial cells with 11,12-EET or H2O2. We found that 11,12-EET and H2O2 exert contrasting effects on JNK activity in endothelial cells in that EET stimulation decreased the JNK-mediated phosphorylation of c-Jun, whereas H2O2 increased kinase activity. Similarly, 11,12-EET, but not H2O2, induced the expression of MKP-1.
      Although our results suggest that EET-mediated alterations in the MKP-1 expression and JNK activity regulate the expression of cyclin D1, we cannot rule out the possibility that additional parallel signaling pathways are also involved. For example, recent reports have suggested that EETs are capable of activating phosphatidylinositol 3-kinase (
      • Chen J.-K.
      • Wang D.-W.
      • Falck J.R.
      • Capdevila J.
      • Harris R.C.
      ), which results in the activation of the protein kinase B/Akt (
      • Chen J.K.
      • Capdevila J.
      • Harris R.C.
      ). The activation of protein kinase B/Akt could contribute to CYP 2C9-induced cell proliferation by inhibiting the glycogen synthase kinase-3β-dependent phosphorylation and degradation of cyclin D1 (
      • Diehl J.A.
      • Cheng M.
      • Roussel M.F.
      • Sherr C.J.
      ) as well as the phosphorylation and degradation of p21Cip1 (
      • Rössig L.
      • Badorff C.
      • Holzmann Y.
      • Zeiher A.M.
      • Dimmeler S.
      ). Indeed, p21Cip1 expression is enhanced in endothelial cells overexpressing CYP 2C9,
      M. Potente, unpublished observations.
      and p21Cip1has been shown to be a positive regulator of cyclin D-dependent kinases and to promote cell cycle progression by acting as an essential assembly factor for cyclin D-CDK complexes (
      • LaBaer J.
      • Garrett M.D.
      • Stevenson L.F.
      • Slingerland J.M.
      • Sandhu C.
      • Chou H.S.
      • Fattaey A.
      • Harlow E.
      ,
      • Cheng M.
      • Olivier P.
      • Diehl J.A.
      • Fero M.
      • Roussel M.F.
      • Roberts J.M.
      • Sherr C.J.
      ,
      • Sherr C.J.
      • Roberts J.M.
      ). A further possibility is that EET signaling involves cross-talk with the epidermal growth factor receptor (
      • Chen J.-K.
      • Wang D.-W.
      • Falck J.R.
      • Capdevila J.
      • Harris R.C.
      ) and that this receptor may function directly as a transcription factor to enhance cyclin D1 expression (
      • Lin S.Y.
      • Makino K.
      • Xia W.
      • Matin A.
      • Wen Y.
      • Kwong K.Y.
      • Bourguignon L.
      • Hung M.C.
      ). Thus, it is certainly feasible that at least part of the proliferative effects of CYP 2C9 overexpression in endothelial cells can also be attributed to the parallel activation of signaling cascades not directly affecting JNK.
      Epoxygenase-derived EETs are now recognized as important modulators of intracellular signal transduction cascades, but it is not clear exactly how EETs can initiate their effects on cell signaling. Two modes of cell activation by EETs have been proposed. The first involves the activation of a putative extra- or intracellular EET receptor (
      • Wong P.Y.
      • Lai P.S.
      • Falck J.R.
      ), and the second involves the incorporation of EETs into the plasma membrane where they may associate with effector molecules such as ADP-ribosyltransferases (
      • Li P.-L.
      • Chen C.-L.
      • Bortell R.
      • Campbell W.B.
      ), the small GTP-binding protein Ras (
      • Muthalif M.M.
      • Uddin M.R.
      • Fatima S.
      • Parmentier J.
      • Khandekar Z.
      • Malik K.U.
      ), or protein kinase A (
      • Imig J.D.
      • Inscho E.W.
      • Deichamnn P.C.
      • Reddy K.M.
      • Falck J.R.
      ). Although the initial steps in the signal cascade remain to be elucidated, the results of the present study clearly demonstrate that CYP epoxygenase-derived EETs induce the expression of the immediate early gene product MKP-1, which dephosphorylates and inactivates JNK, thus enhancing cyclin D1 levels and promoting endothelial cell proliferation.

      Acknowledgments

      We are indebted to Isabel Winter for expert technical assistance.

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