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J. Biol. Chem., Vol. 282, Issue 1, 240-248, January 5, 2007

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Hypoxic Regulation of Id-1 and Activation of the Unfolded Protein Response Are Aberrant in Neuroblastoma^*

From the Department of Medicine, Pharmacology and the New York University Cancer Institute, The New York University School of Medicine, New York City, New York 10016

The Id proteins play an important role in proliferation, differentiation and tumorigenesis. Many tumors are hypoxic, but it is unknown if expression of Id proteins is regulated in hypoxic cells. Here we show that Id-1 is down-regulated in multiple primary, immortalized, and neoplastic hypoxic cell lines, and the transcriptional repressor ATF-3 is both necessary and sufficient for this hypoxia-induced repression of Id-1. Hypoxic up-regulation of ATF-3 is due in part to activation of the unfolded protein response, a cellular stress response. Remarkably, we observe that the unfolded protein response is de-regulated in all neuroblastoma cell lines tested. Indeed, in the absence of ATF-3 the hypoxia-induced transcription factor HIF-1 up-regulates Id-1 in hypoxic neuroblastoma cells. Hypoxic neuroblastoma cells diminish expression of some neuronal differentiation markers, and forced expression of ATF-3 in hypoxic neuroblastoma cells represses Id-1 and prevents the loss of these markers. The divergent regulation of Id proteins in distinct hypoxic cells may explain some of the varied effects hypoxia has on cellular differentiation and proliferation.

Received for publication, August 1, 2006 , and in revised form, October 25, 2006.

^* This work was supported by National Institutes of Health Grant CA89265 and by a New York University Whitehead Fellowship (to L. B. G.). 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.

¹ To whom correspondence should be addressed: Division of Hematology, Dept. of Medicine, New York University School of Medicine, Tisch 401, 550 1st Ave., New York, NY 10016. Tel.: 212-263-8038; Fax: 212-263-8444; E-mail: lawrence.gardner{at}med.nyu.edu.

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