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c-Jun and hypoxia-inducible factor 1 functionally cooperate in hypoxia-induced gene transcription.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2002 Jan; Vol. 22 (1), pp. 12-22. - Publication Year :
- 2002
-
Abstract
- 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-1alpha subunit, nor does it require direct binding of c-Jun to DNA. c-Jun and HIF-1alpha 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 Ser(63) in endothelial cells. This process is involved in its cooperative effect, since specific blockade of the JNK pathway and mutation of c-Jun at Ser(63) and Ser(73) 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.
- Subjects :
- 5' Untranslated Regions metabolism
Cells, Cultured
DNA-Binding Proteins genetics
Endothelial Growth Factors genetics
Endothelial Growth Factors metabolism
Endothelium, Vascular cytology
Genes, Reporter
Helix-Loop-Helix Motifs
Humans
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
Lymphokines genetics
Lymphokines metabolism
Nuclear Proteins genetics
Protein Binding
Proto-Oncogene Proteins c-jun genetics
Recombinant Fusion Proteins metabolism
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
Cell Hypoxia
DNA-Binding Proteins metabolism
Gene Expression Regulation genetics
Nuclear Proteins metabolism
Proto-Oncogene Proteins c-jun metabolism
Transcription Factors
Transcription, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 0270-7306
- Volume :
- 22
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 11739718
- Full Text :
- https://doi.org/10.1128/MCB.22.1.12-22.2002