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It was shown that the Ca2+-ionophore A23187 and the cell permeable Ca2+-chelator BAPTA-am (1,2-bis(2-aminophenoxy)ethane-N,N,N\u2032,N\u2032-tetraacetic acid-acetoxymethyl ester) 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 hypoxiainducible factor-1 (HIF-1) mediated the response to A23187 and BAPTA-am. Although A23187 induced a striking and stable induction of HIF-1\u03b1, BAPTA-am only mediated a fast and transient increase. By using actinomycin D and cycloheximide we showed that A23187 induced HIF-1\u03b1 mRNA expression, whereas BAPTA-am acted after transcription. Although A23187 activated extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK), as well as protein kinase B, it appeared that the enhancement of HIF-1\u03b1 by A23187 was only mediated via the ERK pathway. By contrast, BAPTA-am exerted its effects via inhibition of HIF-prolyl hydroxylase activity and von Hippel-Lindau tumor repressor protein (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. (Blood. 2004;104:3993-4001)<\/jats:p>","DOI":"10.1182\/blood-2004-03-1017","type":"journal-article","created":{"date-parts":[[2004,8,25]],"date-time":"2004-08-25T00:13:16Z","timestamp":1093392796000},"page":"3993-4001","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":39,"title":["Induction of plasminogen activator inhibitor I gene expression by intracellular calcium via hypoxia-inducible factor-1"],"prefix":"10.1182","volume":"104","author":[{"given":"Qing","family":"Liu","sequence":"first","affiliation":[{"name":"From the Institut fu\u0308r Biochemie und Molekulare Zellbiologie, Go\u0308ttingen, Germany; and the Department Chemistry\/Biochemistry, University of Kaiserslautern, Kaiserslautern, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Mo\u0308ller","sequence":"additional","affiliation":[{"name":"From the Institut fu\u0308r Biochemie und Molekulare Zellbiologie, Go\u0308ttingen, Germany; and the Department Chemistry\/Biochemistry, University of Kaiserslautern, Kaiserslautern, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Flu\u0308gel","sequence":"additional","affiliation":[{"name":"From the Institut fu\u0308r Biochemie und Molekulare Zellbiologie, Go\u0308ttingen, Germany; and the Department Chemistry\/Biochemistry, University of Kaiserslautern, Kaiserslautern, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Kietzmann","sequence":"additional","affiliation":[{"name":"From the Institut fu\u0308r Biochemie und Molekulare Zellbiologie, Go\u0308ttingen, Germany; and the Department Chemistry\/Biochemistry, University of Kaiserslautern, Kaiserslautern, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2020021218285672800_REF1","doi-asserted-by":"crossref","unstructured":"Erickson LA, Hekman CM, Loskutoff DJ. 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