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Blood, 15 December 2004, Vol. 104, No. 13, pp. 3993-4001. Prepublished online as a Blood First Edition Paper on August 24, 2004; DOI 10.1182/blood-2004-03-1017. This Article Full Text (PDF) All Versions of this Article: 2004-03-1017v1 104/13/3993    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Liu, Q. Articles by Kietzmann, T. Search for Related Content PubMed PubMed Citation Articles by Liu, Q. Articles by Kietzmann, T. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 17, 2004 Accepted August 10, 2004 Induction of plasminogen activator inhibitor I gene expression by intracellular calcium via hypoxia-inducible factor-1 Qing Liu, Ulrike Moller, Daniela Flugel, and Thomas Kietzmann* Institut fur Biochemie und Molekulare Zellbiologie, Gottingen, Germany Institut fur Biochemie und Molekulare Zellbiologie, Gottingen, Germany; Department of Chemistry/Biochemistry, University of Kaiserslautern, Kaiserslautern, Germany * Corresponding author; email: tkietzm{at}gwdg.de. The plasminogen activator inhibitor-1 (PAI-1) expression can be enhanced by hypoxia and other stimuli leading to the mobilization of intracellular calcium. Thus, it was the aim of the present study to investigate the role of calcium in the hypoxia-dependent PAI-1 expression. It was shown that the Ca2+-ionophore A23187 and the cell permeable Ca2+-chelator BAPTA-AM induced PAI-1 mRNA and protein expression under normoxia and hypoxia in HepG2 cells. Transfection experiments with wild-type and hypoxia response element (HRE) mutated PAI- promoter constructs revealed that the HRE binding hypoxia-inducible factor-1 (HIF-1) mediated the response to A23187 and BAPTA-AM. While A23187 induced a striking and stable induction of HIF-1, BAPTA-AM only mediated a fast and transient increase. By using actinomycin D and cycloheximide we showed that A23187 iduced HIF-1 mRNA expression whereas BAPTA-AM acted posttranscriptionally. Although A23187 activated ERK, JNK and p38 MAPK as well as protein kinase B it appeared that the enhancement of HIF-1 by A23187 was only mediated via the ERK pathway. By contrast, BAPTA-AM exerted its effects via inhibition of HIF-prolyl hydroxylase activity and VHL interaction. Thus, calcium appeared to have a critical role in the regulation of the HIF-system and subsequent activation of the PAI-1 gene expression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Alam, J. Weck, E. Maizels, Y. Park, E. J. Lee, M. Ashcroft, and M. Hunzicker-Dunn Role of the Phosphatidylinositol-3-Kinase and Extracellular Regulated Kinase Pathways in the Induction of Hypoxia-Inducible Factor (HIF)-1 Activity and the HIF-1 Target Vascular Endothelial Growth Factor in Ovarian Granulosa Cells in Response to Follicle-Stimulating Hormone Endocrinology, February 1, 2009; 150(2): 915 - 928. [Abstract] [Full Text] [PDF] M.-T. Lin, I-H. Kuo, C.-C. Chang, C.-Y. Chu, H.-Y. Chen, B.-R. Lin, M. Sureshbabu, H.-J. Shih, and M.-L. Kuo Involvement of Hypoxia-inducing Factor-1{alpha}-dependent Plasminogen Activator Inhibitor-1 Up-regulation in Cyr61/CCN1-induced Gastric Cancer Cell Invasion J. Biol. Chem., June 6, 2008; 283(23): 15807 - 15815. [Abstract] [Full Text] [PDF] H. Liao, M. C. Hyman, D. A. Lawrence, and D. J. Pinsky Molecular regulation of the PAI-1 gene by hypoxia: contributions of Egr-1, HIF-1{alpha}, and C/EBP{alpha} FASEB J, March 1, 2007; 21(3): 935 - 949. [Abstract] [Full Text] [PDF] K. S. Kim, V. Rajagopal, C. Gonsalves, C. Johnson, and V. K. Kalra A Novel Role of Hypoxia-Inducible Factor in Cobalt Chloride- and Hypoxia-Mediated Expression of IL-8 Chemokine in Human Endothelial Cells J. Immunol., November 15, 2006; 177(10): 7211 - 7224. [Abstract] [Full Text] [PDF] T. Acker, J. Fandrey, and H. Acker The good, the bad and the ugly in oxygen-sensing: ROS, cytochromes and prolyl-hydroxylases Cardiovasc Res, July 15, 2006; 71(2): 195 - 207. [Abstract] [Full Text] [PDF] J. Zhou, R. Kohl, B. Herr, R. Frank, and B. Brune Calpain Mediates a von Hippel-Lindau Protein-independent Destruction of Hypoxia-inducible Factor-1{alpha} Mol. Biol. Cell, April 1, 2006; 17(4): 1549 - 1558. [Abstract] [Full Text] [PDF] R. Busca, E. Berra, C. Gaggioli, M. Khaled, K. Bille, B. Marchetti, R. Thyss, G. Fitsialos, L. Larribere, C. Bertolotto, et al. Hypoxia-inducible factor 1{alpha} is a new target of microphthalmia-associated transcription factor (MITF) in melanoma cells J. Cell Biol., July 4, 2005; 170(1): 49 - 59. [Abstract] [Full Text] [PDF]

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