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J. Biol. Chem., Vol. 278, Issue 49, 48690-48695, December 5, 2003

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The von Hippel Lindau/Hypoxia-inducible Factor (HIF) Pathway Regulates the Transcription of the HIF-Proline Hydroxylase Genes in Response to Low Oxygen^*

Luis del Peso¶, María C. Castellanos||**, Elisa Temes||, Silvia Martín-Puig||, Yolanda Cuevas, Gemma Olmos||, and Manuel O. Landázuri||

From the Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo s/n, 28029 Madrid, Spain and ^||Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, Diego de León 62, 28006 Madrid, Spain

Most of the genes induced by hypoxia are regulated by a family of transcription factors termed hypoxia-inducible factors (HIF). Under normoxic conditions, HIF proteins are very unstable due to hydroxylation by a recently described family of proline hydroxylases termed EGL-Nine homologs (EGLN). Upon hydroxylation, HIF is recognized by the product of the tumor suppressor vhl and targeted for proteosomal degradation. Since EGLNs require oxygen to catalize HIF hydroxylation, this reaction does not efficiently occur under low oxygen tension. Thus, under hypoxia, HIF escapes from degradation and transcribes target genes. The mRNA levels of two of the three EGLNs described to date are induced by hypoxia, suggesting that they might be novel HIF target genes; however, no proof for this hypothesis has been reported. Here we show that the induction of EGLN1 and -3 by hypoxia is found in a wide range of cell types. The basal levels of EGLN3 are always well below those of EGLN1 and EGLN2, and its induction by hypoxia is larger than that found for EGLN1. The inhibitor of transcription, actinomycin D, prevents the increase of EGLN3 mRNA induced by hypoxia, indicating that it is due to enhanced gene expression. Interestingly, EGLN1 and EGLN3 mRNAs were also triggered by EGLN inhibitors, suggesting the involvement of HIF in the control of its transcription. In agreement with this possibility, pVHL-deficient cell lines, which present high HIF activity under normoxia, also showed dramatically increased normoxic levels of EGLN3. Moreover, the overexpression of an oxygen-insensitive mutant form of HIF resulted in increased normoxic levels of EGLN3 mRNA. Finally, hypoxic induction of EGLNs was not observed in cells lacking functional HIF.

Received for publication, August 11, 2003 , and in revised form, September 22, 2003.

Note Added in Proof—While this manuscript was under review, Berra et al. (Berra, E., Benizri, E., Ginouves, A., Volmat, V., Roux, C., and Pouyssegar, J. (2003) EMBO J. 22, 4082–4088) reported that inhibition of HIF-1 expression by interference RNA (iRNA) prevented the induction of EGLN1 by hypoxia.

^* This work was supported by Fondo de Investigaciones Sanitarias Grant FIS01/0264 (to L. P.), Comunidad Autónoma de Madrid Grant 08.3/0034.1/2001 (to L. P.), and Ministerio de Ciencia y Tecnología Grants SAF 2002-02344 (to L. P.) and SAF 2001-0215 (to M. O. L.). 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.

These authors contributed equally to this work.

^** Supported by Instituto de Salud Carlos III Grant 01/A009.

^¶ To whom correspondence should be addressed. Tel.: 34-91-5202371; Fax: 34-91-5202374; E-mail: lpeso.hlpr{at}salud.madrid.org.

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