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J. Biol. Chem., Vol. 279, Issue 38, 39223-39231, September 17, 2004

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Induction of ID2 Expression by Hypoxia-inducible Factor-1

A ROLE IN DEDIFFERENTIATION OF HYPOXIC NEUROBLASTOMA CELLS^*

Tobias Löfstedt, Annika Jögi, Mikael Sigvardsson, Katarina Gradin¶, Lorenz Poellinger¶, Sven Påhlman, and Håkan Axelson||

From the Department of Laboratory Medicine, Division of Molecular Medicine, Lund University, University Hospital MAS, S-205 02 Malmö, Sweden, the Department of Medicine, Hematopoietic Stem Cell Laboratory, Lund University, BMC S-221 84 Lund, Sweden, and the ^¶Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, S-171 77 Stockholm, Sweden

ID (inhibitor of differentiation/DNA binding) proteins, frequently deregulated in advanced human malignancies, can participate in multiple fundamental traits of cancer, such as block of differentiation, increased proliferation, tissue invasiveness, and angiogenesis. We have previously demonstrated that hypoxia decreases expression of neuronal marker genes in neuroblastoma, but induces genes expressed in the neural crest, such as ID2. Because of its involvement in normal neural crest development and its ability to inhibit proneuronal bHLH proteins, the hypoxic induction of ID2 was of particular interest. Here we report fast induction kinetics of ID2 expression in hypoxic neuroblastoma cells. The up-regulation of ID2 was abolished by addition of actinomycin D, implicating a hypoxia-driven transcriptional mechanism. Analyzing the ID2 promoter revealed several potential binding sites for hypoxia-inducible factors. Subsequent electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated two functional HIF-1 binding sites within ID2 gene regulatory sequences located at –725 and –1893 relative to the transcriptional initiation point. In transfection assays, DNA constructs of the ID2 promoter, including the functional HIF-1 binding sites, induced luciferase reporter activity in a HIF-1-specific manner. These observations demonstrate that ID2 is actively engaged by hypoxia and represents a novel HIF-1 target. Hypoxia-induced ID2 expression could play a significant role in the previously observed dedifferentiation of hypoxic neuroblastoma cells, which in a clinical setting could lead to less mature and more aggressive tumors.

Received for publication, March 16, 2004 , and in revised form, June 15, 2004.

^* This work was supported by grants from the Swedish Cancer Society, the Children's Cancer Foundation of Sweden, Åke Wiberg's Foundation, HKH Kronprinsessan Lovisas förening för barnasjukvård, Hans von Kantzow's Foundation, Ollie and Elof Ericsson's foundation, the Crafoord Foundation, and Malmö University Hospital Research Funds. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Laboratory Medicine, Division of Molecular Medicine, Lund University, University Hospital MAS, Entrance 78, S-205 02 Malmö, Sweden. Tel.: 46-40337621; Fax: 46-40337322; E-mail: hakan.axelson{at}molmed.mas.lu.se.

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