© 1996 American Heart Association, Inc.
Articles |
Hypoxia and Hypoxia/Reoxygenation Activate Raf-1, Mitogen-Activated Protein Kinase Kinase, Mitogen-Activated Protein Kinases, and S6 Kinase in Cultured Rat Cardiac Myocytes
From the Third Department of Internal Medicine (Y.S., K.T., K.U., T.K., Y.Y.), Faculty of Medicine, University of Tokyo (Japan); the Department of Immunology (Y.S.), School of Medicine, Juntendo University, Tokyo; and the Institute for Adult Diseases (Y.S.), Asahi Life Foundation, Tokyo.
Correspondence to Yoshinori Seko, MD, Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan.
Abstract In response to hypoxia and reoxygenation, mammalian cells are known to express a variety of genes to adapt to these external stresses or lead to further cell damage. We investigated the intracellular signaling cascades in cultured rat cardiac myocytes subjected to hypoxia or hypoxia followed by reoxygenation (hypoxia/reoxygenation). Here, we show that both hypoxia and hypoxia/reoxygenation caused rapid activation of the mitogen-activated protein kinase kinase kinase (MAPKKK) activity of Raf-1. This was followed by the sequential activation of mitogen-activated protein kinase kinase (MAPKK), mitogen-activated protein (MAP) kinases, and S6 kinase (p90rsk). Furthermore, hypoxia caused hyperphosphorylation of Raf-1. The maximal hyperphosphorylation of Raf-1 appeared to be accompanied by a significant decrease in MAPKKK activity. These results strongly suggest the following: (1) Intracellular signals initiated by both hypoxia and hypoxia/reoxygenation converge on Raf-1 and activate its MAPKKK activity. Then, Raf-1 activates downstream serine/threonine kinases including MAPKK, MAP kinases, and p90rsk. (2) Raf-1 is not only located upstream from MAPKK and MAP kinases but also may be phosphorylated by MAP kinases directly or indirectly, and at least Raf-1 kinase activity may be downregulated by this feedback mechanism.
Key Words: redox • serine/threonine kinase • second messenger • phosphorylation • ischemia/reperfusion
This article has been cited by other articles:
 |
|
 |
|
  D. P. Frazier, A. Wilson, C. J. Dougherty, H. Li, N. H. Bishopric, and K. A. Webster PKC-{alpha} and TAK-1 are intermediates in the activation of c-Jun NH2-terminal kinase by hypoxia-reoxygenation Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1675 - H1684. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Maekawa, J.-i. Abe, T. Shishido, S. Itoh, B. Ding, V. K. Sharma, S.-S. Sheu, B. C. Blaxall, and B. C. Berk Inhibiting p90 Ribosomal S6 Kinase Prevents Na+-H+ Exchanger-Mediated Cardiac Ischemia-Reperfusion Injury Circulation, May 30, 2006; 113(21): 2516 - 2523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. DOUGHERTY, L. A. KUBASIAK, D. P. FRAZIER, H. LI, W.-CHENG. XIONG, N. H. BISHOPRIC, and K. A. WEBSTER Mitochondrial signals initiate the activation of c-Jun N-terminal kinase (JNK) by hypoxia-reoxygenation FASEB J, July 1, 2004; 18(10): 1060 - 1070. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Huang, S. B. Petkova, A. W. Cohen, B. Bouzahzah, J. Chan, J.-n. Zhou, S. M. Factor, L. M. Weiss, M. Krishnamachary, S. Mukherjee, et al. Activation of Transcription Factors AP-1 and NF-{kappa}B in Murine Chagasic Myocarditis Infect. Immun., May 1, 2003; 71(5): 2859 - 2867. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Tang, J. L. Arbiser, and S. J. Brandt Phosphorylation by Mitogen-activated Protein Kinase Mediates the Hypoxia-induced Turnover of the TAL1/SCL Transcription Factor in Endothelial Cells J. Biol. Chem., May 17, 2002; 277(21): 18365 - 18372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Song, Y. K. Park, J.-H. Lee, and K. Park Induction of Glucose-regulated Protein 78 by Chronic Hypoxia in Human Gastric Tumor Cells through a Protein Kinase C-{epsilon}/ERK/AP-1 Signaling Cascade Cancer Res., November 1, 2001; 61(22): 8322 - 8330. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I.-K. S. Aggeli, C. Gaitanaki, A. Lazou, and I. Beis Stimulation of multiple MAPK pathways by mechanical overload in the perfused amphibian heart Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2001; 281(5): R1689 - R1698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Mockridge, A. Punn, D. S. Latchman, M. S. Marber, and R. J. Heads PKC-dependent delayed metabolic preconditioning is independent of transient MAPK activation Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H492 - H501. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Kacimi, J. Chentoufi, N. Honbo, C. S. Long, and J. S. Karliner Hypoxia differentially regulates stress proteins in cultured cardiomyocytes: Role of the p38 stress-activated kinase signaling cascade, and relation to cytoprotection Cardiovasc Res, April 1, 2000; 46(1): 139 - 150. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. M. Hernandez, D. J. Discher, N. H. Bishopric, and K. A. Webster Rapid Activation of Neutral Sphingomyelinase by Hypoxia-Reoxygenation of Cardiac Myocytes Circ. Res., February 4, 2000; 86(2): 198 - 204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Karmazyn, X. T. Gan, R. A Humphreys, H. Yoshida, and K. Kusumoto The Myocardial Na+-H+ Exchange : Structure, Regulation, and Its Role in Heart Disease Circ. Res., October 29, 1999; 85(9): 777 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Kunsch and R. M. Medford Oxidative Stress as a Regulator of Gene Expression in the Vasculature Circ. Res., October 15, 1999; 85(8): 753 - 766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. A. Vasilevskaya and P. J. O'Dwyer Effects of Geldanamycin on Signaling through Activator-Protein 1 in Hypoxic HT29 Human Colon Adenocarcinoma Cells Cancer Res., August 1, 1999; 59(16): 3935 - 3940. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Matsui, Y. Ihara, Y. Fujio, K. Kunisada, S. Akira, T. Kishimoto, and K. Yamauchi-Takihara Induction of interleukin (IL)-6 by hypoxia is mediated by nuclear factor (NF)-{kappa}B and NF-IL6 in cardiac myocytes Cardiovasc Res, April 1, 1999; 42(1): 104 - 112. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Montessuit and A. Thorburn Transcriptional Activation of the Glucose Transporter GLUT1 in Ventricular Cardiac Myocytes by Hypertrophic Agonists J. Biol. Chem., March 26, 1999; 274(13): 9006 - 9012. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. H. SCOTT, A. PAUL, C. M. BELHAM, A. J. PEACOCK, R. M. WADSWORTH, G. W. GOULD, D. WELSH, and R. PLEVIN Hypoxic Stimulation of the Stress-activated Protein Kinases in Pulmonary Artery Fibroblasts Am. J. Respir. Crit. Care Med., September 1, 1998; 158(3): 958 - 962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Goussev, V. G. Sharov, H. Shimoyama, M. Tanimura, M. Lesch, S. Goldstein, and H. N. Sabbah Effects of ACE inhibition on cardiomyocyte apoptosis in dogs with heart failure Am J Physiol Heart Circ Physiol, August 1, 1998; 275(2): H626 - H631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Shimizu, M. Yoshiyama, T. Omura, A. Hanatani, S. Kim, K. Takeuchi, H. Iwao, and J. Yoshikawa Activation of mitogen-activated protein kinases and activator protein-1 in myocardial infarction in rats Cardiovasc Res, April 1, 1998; 38(1): 116 - 124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. S. Hanson and E. A. Leibold Regulation of Iron Regulatory Protein 1 during Hypoxia and Hypoxia/Reoxygenation J. Biol. Chem., March 27, 1998; 273(13): 7588 - 7593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Borger and D. A. Essig Induction of HSP 32 gene in hypoxic cardiomyocytes is attenuated by treatment with N-acetyl-L-cysteine Am J Physiol Heart Circ Physiol, March 1, 1998; 274(3): H965 - H973. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Laderoute and K. A. Webster Hypoxia/Reoxygenation Stimulates Jun Kinase Activity Through Redox Signaling in Cardiac Myocytes Circ. Res., March 1, 1997; 80(3): 336 - 344. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. M. Gleadle and P. J. Ratcliffe Induction of Hypoxia-Inducible Factor-1, Erythropoietin, Vascular Endothelial Growth Factor, and Glucose Transporter-1 by Hypoxia: Evidence Against a Regulatory Role for Src Kinase Blood, January 15, 1997; 89(2): 503 - 509. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Das, D. M. Bouchey, M. J. Moore, D. C. Hopkins, R. A. Nemenoff, and K. R. Stenmark Hypoxia-induced Proliferative Response of Vascular Adventitial Fibroblasts Is Dependent on G Protein-mediated Activation of Mitogen-activated Protein Kinases J. Biol. Chem., May 4, 2001; 276(19): 15631 - 15640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. N. Moor, X. T. Gan, M. Karmazyn, and L. Fliegel Activation of Na+/H+ Exchanger-directed Protein Kinases in the Ischemic and Ischemic-reperfused Rat Myocardium J. Biol. Chem., May 4, 2001; 276(19): 16113 - 16122. [Abstract] [Full Text] [PDF]
|
|