[en] Oxygen-dependent regulation of HIF-1 activity occurs at multiple levels in vivo. The mechanisms regulating HIF-1alpha protein expression have been most extensively analyzed but the ones modulating HIF-1 transcriptional activity remain unclear. Changes in the phosphorylation and/or redox status of HIF-1alpha certainly play a role. Here, we show that ionomycin could activate HIF-1 transcriptional activity in a way that was additive to the effect of hypoxia without affecting HIF-1alpha protein level. In addition, a calmodulin dominant negative mutant and W7, a calmodulin antagonist, as well as BAPTA, an intracellular calcium chelator, inhibited the hypoxia-induced HIF-1 activation. These results indicate that elevated calcium in hypoxia could participate in HIF-1 activation. Furthermore, ERK but not JNK phosphorylation was evidenced in both conditions, ionomycin and hypoxia. PD98059, an inhibitor of the ERK pathway as well as a ERK1 dominant negative mutant also blocked HIF-1 activation by hypoxia and by ionomycin. A MEKK1 (a kinase upstream of JNK) dominant negative mutant had no effect. In addition, BAPTA, calmidazolium, a calmodulin antagonist and PD98059 inhibited VEGF secretion by hypoxic HepG2. All together, these results suggest that calcium and calmodulin would act upstream of ERK in the hypoxia signal transduction pathway.
Mottet, Denis ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases
Michel, Gaetan
Renard, Patricia
Ninane, Noelle
Raes, Martine
Michiels, Carine
Language :
English
Title :
Role of ERK and calcium in the hypoxia-induced activation of HIF-1.
Publication date :
2003
Journal title :
Journal of Cellular Physiology
ISSN :
0021-9541
eISSN :
1097-4652
Publisher :
Wiley Liss, Inc., New York, United States - New York
Volume :
194
Issue :
1
Pages :
30-44
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] Fonds pour Recherche dans l'Industrie et l'Agriculture, Belgique BELSPO - SPP Politique scientifique - Service Public Fédéral de Programmation Politique scientifique
Agani F, Semenza GL. 1998. Mersalyl is a novel inducer of vascular endothelial growth factor gene expression and hypoxia-inducible factor 1 activity. Mol Pharmacol 54:749-754.
Baek SH, Lee UY, Park EM, Han MY, Lee YS, Park YM. 2001. Role of protein kinase Cdelta in transmitting hypoxia signal to HSF and HIF-1. J Cell Physiol 188:223-235.
Baudier J, Bergeret E, Bertacchi N, Weintraub H, Gagnon J, Garin J. 1995. Interactions of myogenic bHLH transcription factors with calcium-binding calmodulin and S100a (alpha alpha) proteins. Biochemistry 34:7834-7846.
Carrero P, Okamoto K, Coumailleau P, O'Brien S, Tanaka H, Poellinger L. 2000. Redox-regulated recruitment of the transcriptional coactivators CREB-binding protein and SRC-1 to hypoxia-inducible factor 1alpha. Mol Cell Biol 20:402-415.
Chao TS, Byron KL, Lee KM, Villereal M, Rosner MR. 1992. Activation of MAP kinases by calcium-dependent and calcium-independent pathways. Stimulation by thapsigargin and epidermal growth factor. J Biol Chem 267:19876-19883.
Conrad PW, Freeman TL, Beitner-Johnson D, Millhorn D. 1999a. EPAS1 trans-activation during hypoxia requires p42/p44 MAPK. J Biol Chem 274:33709-33713.
Conrad PW, Rust RT, Han J, Millhorn DE, Beitner-Johnson D. 1999b. Selective activation of p38alpha and p38gamma by hypoxia. J Biol Chem 274:23570-23576.
Damert A, Ikeda E, Risau W. 1997. Activator-protein-1 binding potentiates the hypoxia-inducible factor-1-mediated hypoxia-induced transcriptional activation of vascular-endothelial growth factor expression in C6 glioma cells. Biochem J 327:419-423.
Dibbens JA, Miller DL, Damert A, Risau W, Vadas MA, Goodall GJ. 1999. Hypoxic regulation of vascular endothelial growth factor mRNA stability requires the cooperation of multiple RNA elements. Mol Biol Cell 10:907-919.
Egea J, Espinet C, Comella JX. 1999. Calcium influx activates extracellular-regulated kinase/mitogen-activated protein kinase pathway through a calmodulin-sensitive mechanism in PC12 cells. J Biol Chem 274:75-85.
Ema M, Hirota K, Mimura J, Abe H, Yodoi J, Sogawa K, Poellinger L, Fujii-Kuriyama Y. 1999. Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: Their stabilization and redox signal-induced interaction with CBP/p300. EMBO J 18:1905-1914.
Enslen H, Tokumitsu H, Stork PJ, Davis RJ, Soderling TR. 1996. Regulation of mitogen-activated protein kinases by a calcium/calmodulin-dependent protein kinase cascade. Proc Natl Acad Sci USA 93:10803-10808.
Farnsworth CL, Freshney NW, Rosen LB, Ghosh A, Greenberg ME, Feig LA. 1995. Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF. Nature 376:524-527.
Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL. 1999. Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. Cancer Res 59:3915-3918.
Frodin M, Sekine N, Roche E, Filloux C, Prentki M, Wollheim CB, Van Obberghen E. 1995. Glucose, other secretagogues, and nerve growth factor stimulate mitogen-activated protein kinase in the insulin-secreting beta-cell line, INS-1. J Biol Chem 270:7882-7889.
Frost JA, Geppert TD, Cobb MH, Feramisco JR. 1994. A requirement for extracellular signal-regulated kinase (ERK) function in the activation of AP-1 by Ha-Ras, phorbol 12-myristate 13-acetate, and serum. Proc Natl Acad Sci USA 91:3844-3848.
Frost JA, Steen H, Shapiro P, Lewis T, Ahn N, Shaw PE, Cobb MH. 1997. Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins. EMBO J 16:6426-6438.
Hirota K, Semenza GL. 2001. Rac1 activity is required for the activation of hypoxia-inducible factor 1. J Biol Chem 276:21166-21172.
Hook SS, Means AR. 2001. Ca(2+)/CaM-dependent kinases: From activation to function. Annu Rev Pharmacol Toxicol 41:471-505.
Huang LE, Gu J, Schau M, Bunn HF. 1998. Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 95:7987-7992.
Hur E, Chang KY, Lee E, Lee SK, Park H. 2001. Mitogen-activated protein kinase kinase inhibitor PD98059 blocks the trans-activation but not the stabilization or DNA binding ability of hypoxia-inducible factor-1alpha. Mol Pharmacol 59:1216-1224.
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG. 2001. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing. Science 292:464-468.
Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ. 2001. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468-472.
Kallio PJ, Okamoto K, O'Brien S, Carrero P, Makino Y, Tanaka H, Poellinger L. 1998. Signal transduction in hypoxic cells: Inducible nuclear translocation and recruitment of the CBP/p300 coactivator by the hypoxia-inducible factor-1alpha. EMBO J 17:6573-6586.
Kallio PJ, Wilson WJ, O'Brien S, Makino Y, Poellinger L. 1999. Regulation of the hypoxia-inducible transcription factor 1alpha by the ubiquitin-proteasome pathway. J Biol Chem 274:6519-6525.
Kamura T, Sato S, Iwai K, Czyzyk-Krzeska M, Conaway RC, Conaway JW. 2000. Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex. Proc Natl Acad Sci USA 97:10430-10435.
Karin M, Hunter T. 1995. Transcriptional control by protein phosphorylation: Signal transmission from the cell surface to the nucleus. Curr Biol 5:747-757.
Lee YJ, Corry PM. 1999. Hypoxia-induced bFGF gene expression is mediated through the JNK signal transduction pathway. Mol Cell Biochem 202:1-8.
Lee SA, Park JK, Kang EK, Bae HR, Bae KW, Park HT. 2000. Calmodulin-dependent activation of p38 and p42/44 mitogenactivated protein kinases contributes to c-fos expression by calcium in PC12 cells: Modulation by nitric oxide. Mol Brain Res 75:16-24.
Levy AP, Levy NS, Wegner S, Goldberg MA. 1995. Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J Biol Chem 270:13333-13340.
Liu Y, Cox SR, Morita T, Kourembanas S. 1995. Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5′ enhancer. Circ Res 77:638-643.
Lo LW, Cheng JJ, Chiu JJ, Wung BS, Liu YC, Wang DL. 2001. Endothelial exposure to hypoxia induces Egr-1 expression involving PKCalpha-mediated Ras/Raf-1/ERK1/2 pathway. J Cell Physiol 188:304-312.
Masson N, Williman C, Maxwell PH, Pugh CW, Ratcliffe PJ. 2001. Independent function of two destruction domains in hypoxia-inducible factor - A chains activated by prolyl hydroxylation. EMBO J 20:5197-5206.
Maxwell PH, Wiesener MS, Chang GW, clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ. 1999. The tumour suppressor protein VHL tragets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271-275.
Mazure N, Chen Y, Laderoute K, Giaccia A. 1997. Induction of vascular endothelial growth factor by hypoxia is modulated by a phosphatidylinositol 3-kinase/Akt signaling pathway in Ha-ras-transformed cells through a hypoxia inducible factor-1 transcriptional element. Blood 90:3322-3331.
Millhorn DE, Raymond R, Conforti L, Zhu W, Beitner-Johnson D, Filisko T, Genter MB, Kobayashi S, Peng M. 1997. Regulation of gene expression for tyrosine hydroxylase in oxygen sensitive cells by hypoxia. Kidney Int 51:527-535.
Minet E, Mottet D, Michel G, Roland I, Raes M, Remacle J, Michiels C. 1999. Hypoxia-induced activation of HIF-1: Role of HIF-1alpha-Hsp90 interaction. FEBS Lett 460:251-256.
Minet E, Arnould T, Michel G, Roland I, Mottet D, Raes M, Remacle J, Michiels C. 2000. ERK activation upon hypoxia: Involvement in HIF-1 activation. FEBS Lett 468:53-58.
Minet E, Michel G, Mottet D, Piret JP, Barbieux A, Raes M, Michiels C. 2001. c-JUN gene induction and AP-1 activity is regulated by a JNK-dependent pathway in hypoxic HepG2 cells. Exp Cell Res 265:114-124.
Mukhopadhyay D, Tsiokas L, Zhou XM, Foster D, Brugge JS, Sukhatme VP. 1995. Hypoxic induction of human vascular endothelial growth factor expression through c-Src activation. Nature 375:577-591.
Muller J, Krauss B, Kaltschmidt C, Baeuerle P, Rupec R. 1997. Hypoxia induces c-fos transcription via a mitogen-activated protein kinase-dependent pathway. J Biol Chem 272:23435-23439.
Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG. 2000. Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2:423-427.
Onions J, Hermann S, Grundstrom T. 1997. Basic helix-loop-helix protein sequences determining differential inhibition by calmodulin and S-100 proteins. J Biol Chem 272:23930-23937.
Onions J, Hermann S, Grundstrom T. 2000. A novel type of calmodulin interaction in the inhibition of basic helix-loop-helix transcription factors. Biochemistry 39:4366-4374.
Raymond R, Millhorn D. 1997. Regulation of tyrosine hydroxylase gene expression during hypoxia: Role of Ca2+ and PKC. Kidney Int 51:536-541.
Renard P, Ernest I, Houbion A, Art M, Le Calvez H, Raes M, Remacle J. 2001. Development of a sensitive multi-well colorimetric assay for active NFkappaB. Nucleic Acids Res 29:E21-E25.
Richard DE, Berra E, Gothie E, Roux D, Pouyssegur J. 1999. p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. J Biol Chem 274:32631-32637.
Rosen LB, Ginty DD, Weber MJ, Greenberg ME. 1994. Membrane depolarization and calcium influx stimulate MEK and MAP kinase via activation of Ras. Neuron 12:1207-1221.
Salceda S, Beck I, Srinivas V, Caro J. 1997. Complex role of protein phosphorylation in gene activation by hypoxia. Kidney Int 51:556-559.
Scott PH, Paul A, Belham CM, Peacock AJ, Wadsworth RM, Gould GW, Welsh D, Plevin R. 1998. Hypoxic stimulation of the stress-activated protein kinases in pulmonary artery fibroblasts. Am J Respir Crit Care Med 158:958-962.
Semenza GL. 1999. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15:551-578.
Tanimoto K, Makino Y, Pereira T, Poellinger L. 2000. Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J 19:4298-4309.
Wang GL, Jiang BH, Rue EA, Semenza GL. 1995. Hypoxia-Inducible Factor-1 is a basic-helix-loop-helix-PAS hetrodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510-5514.
Wang KL, Khan MT, Roufogalis BD. 1997. Identification and characterization of a calmodulin-binding domain in Ral-A, a Ras-related GTP-binding protein purified from human erythrocyte membrane. J Biol Chem 272:16002-16009.
Wenger RH, Gassmann M. 1997. Oxygen(e)s and the hypoxia-inducible factor-1. Biol Chem 378:609-616.
White FC, Carroll SM, Kamps MP. 1995. VEGF mRNA is reversibly stabilized by hypoxia and persistently stabilized in VEGF-overexpressing human tumor cell lines. Growth Factors 12:289-301.
Xia XM, Fakler B, Rivard A, Wayman G, Hjohnson-Pais T, keen JE, Ishii T, hirschberg B, Bond CT, Lutsenko S, Maylie J, Adelman JP. 1998. Mechanism of calcium gating in small-conductance calcium-activated potassium channels. Nature 395:503-507.
