|
|
|
|||||||
|
|||||||||
J Biol Chem, Vol. 274, Issue 8, 4764-4769, February 19, 1999
From the Departments of A common feature of most isolated cell systems is
low or undetectable levels of bioactive cytochrome P450. We therefore
developed stable transfectants of the renal epithelial cell line,
LLCPKcl4, that expressed an active regio- and enantioselective
arachidonic acid (AA) epoxygenase. Site-specific mutagenesis was used
to convert bacterial P450 BM-3 into an active regio- and
stereoselective 14S,15R-epoxygenase (F87V
BM-3). In clones expressing F87V BM-3 (F87V BM-3 cells), exogenous AA
induced significant 14S,15R-epoxyeicosatrienoic acid (EET) production (241.82 ng/108 cells, >97% of
total EETs), whereas no detectable EETs were seen in cells transfected
with vector alone. In F87V BM-3 cells, AA stimulated
[3H]thymidine incorporation and increased cell
proliferation, which was blocked by the tyrosine kinase inhibitor,
genistein, by the phosphatidylinositol 3 (PI-3) kinase inhibitors,
wortmannin and LY294002, and by the mitogen-activated protein kinase
kinase inhibitor, PD98059. AA also induced tyrosine phosphorylation of
extracellular signal-regulated kinase (ERK) and PI-3 kinase that was
inhibited by the cytochrome P450 BM-3 inhibitor, 17-ODYA. Epidermal
growth factor (EGF) increased EET production in F87V BM-3 cells, which was completely abolished by pretreatment with either 17-ODYA or the
phospholipase A2 (PLA2) inhibitor, quinacrine.
Compared with vector-transfected cells, F87 BM-3 transfected cells
demonstrated marked increases in both the extent and sensitivity of DNA
synthesis in response to EGF. These changes occurred in the absence of
significant differences in EGF receptor expression. As seen with
exogenous AA, EGF increased ERK tyrosine phosphorylation to a
significantly greater extent in F87V BM-3 cells than in
vector-transfected cells. Furthermore, in these control cells, neither
17-ODYA nor quinacrine inhibited EGF-induced ERK tyrosine
phosphorylation. On the other hand, in F87V BM-3 cells, both inhibitors
reduced ERK tyrosine phosphorylation to levels indistinguishable from
that seen in cells transfected with vector alone.
These studies provide the first unequivocal evidence for a role for the
AA epoxygenase pathway and endogenous EET synthesis in EGF-mediated
signaling and mitogenesis and provide compelling evidence for the
PLA2-AA-EET pathway as an important
intracellular-signaling pathway in cells expressing high levels of
cytochrome P450 epoxygenase.
Transfection of an Active Cytochrome P450 Arachidonic Acid
Epoxygenase Indicates That 14,15-Epoxyeicosatrienoic Acid Functions as
an Intracellular Second Messenger in Response to Epidermal Growth
Factor
,,¶, and
Medicine and
¶ Biochemistry, Vanderbilt University, Nashville, Tennessee 37232 and the § Department of Biochemistry, University of
Texas Southwestern, Dallas, Texas 75235
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  A. C. Webler, U. R. Michaelis, R. Popp, E. Barbosa-Sicard, A. Murugan, J. R. Falck, B. Fisslthaler, and I. Fleming Epoxyeicosatrienoic acids are part of the VEGF-activated signaling cascade leading to angiogenesis Am J Physiol Cell Physiol, November 1, 2008; 295(5): C1292 - C1301. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-K. Chen, J. Chen, J. D. Imig, S. Wei, D. L. Hachey, J. S. Guthi, J. R. Falck, J. H. Capdevila, and R. C. Harris Identification of Novel Endogenous Cytochrome P450 Arachidonate Metabolites with High Affinity for Cannabinoid Receptors J. Biol. Chem., September 5, 2008; 283(36): 24514 - 24524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Morin, M. Sirois, V. Echave, M. M. Gomes, and E. Rousseau EET Displays Anti-Inflammatory Effects in TNF-{alpha} Stimulated Human Bronchi: Putative Role of CPI-17 Am. J. Respir. Cell Mol. Biol., February 1, 2008; 38(2): 192 - 201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Irusta, M.J. Murphy, W.D. Perez, and J.D. Hennebold Dynamic expression of epoxyeicosatrienoic acid synthesizing and metabolizing enzymes in the primate corpus luteum Mol. Hum. Reprod., August 1, 2007; 13(8): 541 - 548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yang, L. Lin, J.-X. Chen, C. R. Lee, J. M. Seubert, Y. Wang, H. Wang, Z.-R. Chao, D.-D. Tao, J.-P. Gong, et al. Cytochrome P-450 epoxygenases protect endothelial cells from apoptosis induced by tumor necrosis factor-{alpha} via MAPK and PI3K/Akt signaling pathways Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H142 - H151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Nusing, H. Schweer, I. Fleming, D. C. Zeldin, and M. Wegmann Epoxyeicosatrienoic acids affect electrolyte transport in renal tubular epithelial cells: dependence on cyclooxygenase and cell polarity Am J Physiol Renal Physiol, July 1, 2007; 293(1): F288 - F298. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Morin, M. Sirois, V. Echave, M. M. Gomes, and E. Rousseau Epoxyeicosatrienoic Acid Relaxing Effects Involve Ca2+-Activated K+ Channel Activation and CPI-17 Dephosphorylation in Human Bronchi Am. J. Respir. Cell Mol. Biol., May 1, 2007; 36(5): 633 - 641. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Chen, J.-K. Chen, J. R. Falck, S. Anjaiah, J. H. Capdevila, and R. C. Harris Mitogenic Activity and Signaling Mechanism of 2-(14,15- Epoxyeicosatrienoyl)Glycerol, a Novel Cytochrome P450 Arachidonate Metabolite Mol. Cell. Biol., April 15, 2007; 27(8): 3023 - 3034. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Gatica, M. C. Aguilera, D. Contador, G. Loyola, C. O. Pinto, L. Amigo, J. E. Tichauer, S. Zanlungo, and M. Bronfman P450 CYP2C epoxygenase and CYP4A {omega}-hydroxylase mediate ciprofibrate-induced PPAR{alpha}-dependent peroxisomal proliferation J. Lipid Res., April 1, 2007; 48(4): 924 - 934. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Spector and A. W. Norris Action of epoxyeicosatrienoic acids on cellular function Am J Physiol Cell Physiol, March 1, 2007; 292(3): C996 - C1012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Dhanasekaran, R. Al-Saghir, B. Lopez, D. Zhu, D. D. Gutterman, E. R. Jacobs, and M. Medhora Protective effects of epoxyeicosatrienoic acids on human endothelial cells from the pulmonary and coronary vasculature Am J Physiol Heart Circ Physiol, August 1, 2006; 291(2): H517 - H531. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Chen, J.-K. Chen, E. G. Neilson, and R. C. Harris Role of EGF Receptor Activation in Angiotensin II-Induced Renal Epithelial Cell Hypertrophy J. Am. Soc. Nephrol., June 1, 2006; 17(6): 1615 - 1623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Christmas, K. Tolentino, V. Primo, K. Z. Berry, R. C. Murphy, M. Chen, D. M. Lee, and R. J. Soberman Cytochrome P-450 4F18 Is the Leukotriene B4 {omega}-1/{omega}-2 Hydroxylase in Mouse Polymorphonuclear Leukocytes: IDENTIFICATION AS THE FUNCTIONAL ORTHOLOGUE OF HUMAN POLYMORPHONUCLEAR LEUKOCYTE CYP4F3A IN THE DOWN-REGULATION OF RESPONSES TO LTB4 J. Biol. Chem., March 17, 2006; 281(11): 7189 - 7196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. B. Campbell, B. B. Holmes, J. R. Falck, J. H. Capdevila, and K. M. Gauthier Regulation of potassium channels in coronary smooth muscle by adenoviral expression of cytochrome P-450 epoxygenase Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H64 - H71. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wang, X. Wei, X. Xiao, R. Hui, J. W. Card, M. A. Carey, D. W. Wang, and D. C. Zeldin Arachidonic Acid Epoxygenase Metabolites Stimulate Endothelial Cell Growth and Angiogenesis via Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt Signaling Pathways J. Pharmacol. Exp. Ther., August 1, 2005; 314(2): 522 - 532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Pozzi, I. Macias-Perez, T. Abair, S. Wei, Y. Su, R. Zent, J. R. Falck, and J. H. Capdevila Characterization of 5,6- and 8,9-Epoxyeicosatrienoic Acids (5,6- and 8,9-EET) as Potent in Vivo Angiogenic Lipids J. Biol. Chem., July 22, 2005; 280(29): 27138 - 27146. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-G. Jiang, C.-L. Chen, J. W. Card, S. Yang, J.-X. Chen, X.-N. Fu, Y.-G. Ning, X. Xiao, D. C. Zeldin, and D. W. Wang Cytochrome P450 2J2 Promotes the Neoplastic Phenotype of Carcinoma Cells and Is Up-regulated in Human Tumors Cancer Res., June 1, 2005; 65(11): 4707 - 4715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-S. Wang, F. Zhang, M. Jiang, M.-H. Wang, B. A. Zand, N. G. Abraham, A. Nasjletti, and M. Laniado-Schwartzman Transfection and Functional Expression of CYP4A1 and CYP4A2 Using Bicistronic Vectors in Vascular Cells and Tissues J. Pharmacol. Exp. Ther., December 1, 2004; 311(3): 913 - 920. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wei, D.-H. Lin, R. Kemp, G. S.S. Yaddanapudi, A. Nasjletti, J. R. Falck, and W.-H. Wang Arachidonic Acid Inhibits Epithelial Na Channel Via Cytochrome P450 (CYP) Epoxygenase-dependent Metabolic Pathways J. Gen. Physiol., November 29, 2004; 124(6): 719 - 727. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Li, Y. Wei, and W.-H. Wang Dietary K intake regulates the response of apical K channels to adenosine in the thick ascending limb Am J Physiol Renal Physiol, November 1, 2004; 287(5): F954 - F959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wang, L. Lin, J. Jiang, Y. Wang, Z. Y. Lu, J. A. Bradbury, F. B. Lih, D. W. Wang, and D. C. Zeldin Up-Regulation of Endothelial Nitric-Oxide Synthase by Endothelium-Derived Hyperpolarizing Factor Involves Mitogen-Activated Protein Kinase and Protein Kinase C Signaling Pathways J. Pharmacol. Exp. Ther., November 1, 2003; 307(2): 753 - 764. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Ladd, L. Du, J. H. Capdevila, R. Mernaugh, and D. S. Keeney Epoxyeicosatrienoic Acids Activate Transglutaminases in Situ and Induce Cornification of Epidermal Keratinocytes J. Biol. Chem., September 12, 2003; 278(37): 35184 - 35192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Medhora, J. Daniels, K. Mundey, B. Fisslthaler, R. Busse, E. R. Jacobs, and D. R. Harder Epoxygenase-driven angiogenesis in human lung microvascular endothelial cells Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H215 - H224. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Zhang and D. R. Harder Cerebral Capillary Endothelial Cell Mitogenesis and Morphogenesis Induced by Astrocytic Epoxyeicosatrienoic Acid Stroke, December 1, 2002; 33(12): 2957 - 2964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Fang, N. L. Weintraub, C. L. Oltman, L. L. Stoll, T. L. Kaduce, S. Harmon, K. C. Dellsperger, C. Morisseau, B. D. Hammock, and A. A. Spector Human coronary endothelial cells convert 14,15-EET to a biologically active chain-shortened epoxide Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2306 - H2314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J. Alkayed, T. Goyagi, H.-D. Joh, J. Klaus, D. R. Harder, R. J. Traystman, and P. D. Hurn Neuroprotection and P450 2C11 Upregulation After Experimental Transient Ischemic Attack Stroke, June 1, 2002; 33(6): 1677 - 1684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Cussac, S. Schaak, C. Denis, and H. Paris alpha 2B-Adrenergic Receptor Activates MAPK via a Pathway Involving Arachidonic Acid Metabolism, Matrix Metalloproteinases, and Epidermal Growth Factor Receptor Transactivation J. Biol. Chem., May 24, 2002; 277(22): 19882 - 19888. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Fleming To Move or Not To Move?: Cytochrome P450 Products and Cell Migration Circ. Res., May 17, 2002; 90(9): 936 - 938. [Full Text] [PDF]
|
|
|
|
|
|
M. Potente, U. R. Michaelis, B. Fisslthaler, R. Busse, and I. Fleming 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 J. Biol. Chem., May 3, 2002; 277(18): 15671 - 15676. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-K. Chen, J. Capdevila, and R. C. Harris Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate epoxygenase metabolites in epithelial cells PNAS, April 30, 2002; 99(9): 6029 - 6034. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Roman P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function Physiol Rev, January 1, 2002; 82(1): 131 - 185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Fleming Cytochrome P450 and Vascular Homeostasis Circ. Res., October 26, 2001; 89(9): 753 - 762. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-K. Chen, J. Capdevila, and R. C. Harris Cytochrome P450 Epoxygenase Metabolism of Arachidonic Acid Inhibits Apoptosis Mol. Cell. Biol., September 15, 2001; 21(18): 6322 - 6331. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Stockton and B. S. Jacobson Modulation of Cell-Substrate Adhesion by Arachidonic Acid: Lipoxygenase Regulates Cell Spreading and ERK1/2-inducible Cyclooxygenase Regulates Cell Migration in NIH-3T3 Fibroblasts Mol. Biol. Cell, July 1, 2001; 12(7): 1937 - 1956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-K. Chen, J. Zimpelmann, R. C. Harris, and K. D. Burns Angiotensin IV induces tyrosine phosphorylation of focal adhesion kinase and paxillin in proximal tubule cells Am J Physiol Renal Physiol, June 1, 2001; 280(6): F980 - F988. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. R. Jacobs and D. C. Zeldin The lung HETEs (and EETs) up Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H1 - H10. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-C. Tsao, J. Foley, S. J. Coulter, R. Maronpot, D. C. Zeldin, and J. A. Goldstein CYP2C40, a Unique Arachidonic Acid 16-Hydroxylase, Is the Major CYP2C in Murine Intestinal Tract Mol. Pharmacol., August 1, 2000; 58(2): 279 - 287. [Abstract] [Full Text]
|
|
|
|
|
|
J.-K. Chen, J. Capdevila, and R. C. Harris Overexpression of C-terminal Src Kinase Blocks 14,15-Epoxyeicosatrienoic Acid-induced Tyrosine Phosphorylation and Mitogenesis J. Biol. Chem., April 28, 2000; 275(18): 13789 - 13792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. H. Munzenmaier and D. R. Harder Cerebral microvascular endothelial cell tube formation: role of astrocytic epoxyeicosatrienoic acid release Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1163 - H1167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Capdevila, J. R. Falck, and R. C. Harris Cytochrome P450 and arachidonic acid bioactivation: molecular and functional properties of the arachidonate monooxygenase J. Lipid Res., February 1, 2000; 41(2): 163 - 181. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Zhang, L. L. Cribbs, and J. Satin Arachidonic acid modulation of alpha 1H, a cloned human T-type calcium channel Am J Physiol Heart Circ Physiol, January 1, 2000; 278(1): H184 - H193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sanchez and J. J. Moreno Role of EP1 and EP4 PGE2 subtype receptors in serum-induced 3T6 fibroblast cycle progression and proliferation Am J Physiol Cell Physiol, February 1, 2002; 282(2): C280 - C288. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |