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Prepublished online as a Blood First Edition Paper on May 31, 2002; DOI 10.1182/blood-2001-12-0169. This Article Full Text (PDF) All Versions of this Article: 2001-12-0169v1 100/7/2623    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 Stolze, I. Articles by Fandrey, J. Search for Related Content PubMed PubMed Citation Articles by Stolze, I. Articles by Fandrey, J. Social Bookmarking                   What's this? Submitted December 5, 2001 Accepted May 4, 2002 Hypoxia inducible erythropoietin gene expression in human neuroblastoma cells Ineke Stolze, Utta Berchner-Pfannschmidt, Patricia Freitag, Christoph Wotzlaw, Jochen Rossler, Stilla Frede, Helmut Acker, and Joachim Fandrey* Institut fur Physiologie, Universitat Essen, Essen, Germany Max-Planck-Institut fur molekulare Physiologie, Dortmund, Germany Universitats-Kinderklinik Freiburg, Freiburg, Germany * Corresponding author; email: joachim.fandrey{at}uni-essen.de. Two human neuroblastoma (NB) cell lines, SH-SY5Y and Kelly, were found to express the gene for erythropoietin (EPO) in an O2-dependent manner. However, NB cells exhibited maximal EPO production under lower pO2 values than the well characterized hepatoma cell line HepG2. This maximal EPO expression was preceded by accumulation of the O2-sensitive -subunit of the heterodimeric transcription factor complex hypoxia inducible factor 1 (HIF-1). Western analysis revealed that the amount of the ß-subunit of HIF-1, identical to ARNT1 (aryl hydrocarbon receptor nuclear translocator), and the homologue ARNT2 increased in nuclear extracts from SH-SY5Y cells exposed to anoxia. In neuronal cells ARNT1 and ARNT2 can form a heterodimer with HIF-1 generating a functional HIF-1 complex. Using the hypoxia response element (HRE) of the human EPO enhancer, electrophoretic mobility shift assays showed accumulation and binding of HIF-1 complexes containing both ARNT1 and ARNT2 in NB cells. In addition to the HIF-1 complex, the hepatocyte nuclear factor 4 (HNF4) is known to be indispensable for hypoxia-induced EPO gene expression in hepatoma cells. As shown by Western analysis and PCR, NB cells neither express HNF4 nor the splicing variant HNF47 and thus express EPO in an HNF4 independent manner. Taken together, we provide a new in vitro model to study the mechanism of tissue specific, hypoxia-inducible EPO gene expression. 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