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Molecular and Cellular Biology, January 2002, p. 12-22, Vol. 22, No. 1
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.1.12-22.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

c-Jun and Hypoxia-Inducible Factor 1 Functionally Cooperate in Hypoxia-Induced Gene Transcription

Arántzazu Alfranca, M. Dolores Gutiérrez, Alicia Vara, Julián Aragonés, Felipe Vidal, and Manuel O. Landázuri*

Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma de Madrid, 28006 Madrid, Spain

Received 2 August 2001/ Accepted 20 September 2001

Under low-oxygen conditions, cells develop an adaptive program that leads to the induction of several genes, which are transcriptionally regulated by hypoxia-inducible factor 1 (HIF-1). On the other hand, there are other factors which modulate the HIF-1-mediated induction of some genes by binding to cis-acting motifs present in their promoters. Here, we show that c-Jun functionally cooperates with HIF-1 transcriptional activity in different cell types. Interestingly, a dominant-negative mutant of c-Jun which lacks its transactivation domain partially inhibits HIF-1-mediated transcription. This cooperative effect is not due to an increase in the nuclear amount of the HIF-1{alpha} subunit, nor does it require direct binding of c-Jun to DNA. c-Jun and HIF-1{alpha} are able to associate in vivo but not in vitro, suggesting that this interaction involves the participation of additional proteins and/or a posttranslational modification of these factors. In this context, hypoxia induces phosphorylation of c-Jun at Ser63 in endothelial cells. This process is involved in its cooperative effect, since specific blockade of the JNK pathway and mutation of c-Jun at Ser63 and Ser73 impair its functional cooperation with HIF-1. The functional interplay between c-Jun and HIF-1 provides a novel insight into the regulation of some genes, such as the one for VEGF, which is a key regulator of tumor angiogenesis.

* Corresponding author. Mailing address: Servicio de Inmunología, Hospital de la Princesa, Diego de León 62, 28006 Madrid, Spain. Phone: 34-91-5202662. Fax: 34-91-5202374. E-mail: mortiz{at}hlpr.insalud.es.

Molecular and Cellular Biology, January 2002, p. 12-22, Vol. 22, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.1.12-22.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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