The regulation of hypoxic genes by calcium involves c-Jun/AP-1, which cooperates with hypoxia-inducible factor 1 in response to hypoxia.

Abstract

Hypoxia causes the accumulation of the transcription factor hypoxia-inducible factor 1 (HIF-1), culminating in the expression of hypoxia-inducible genes such as those for vascular endothelial growth factor (VEGF) and NDRG-1/Cap43. Previously, we have demonstrated that intracellular calcium (Ca(2+)) is required for the expression of hypoxia-inducible genes. Here we found that, unlike with hypoxia or hypoxia-mimicking conditions, the elevation of intracellular Ca(2+) neither induced the HIF-1alpha protein nor stimulated HIF-1-dependent transcription. Furthermore, the elevation of intracellular Ca(2+) induced NDRG-1/Cap43 mRNA in HIF-1alpha-deficient cells. It also increased levels of c-Jun protein, causing its phosphorylation. The protein kinase inhibitor K252a abolished c-Jun induction and activator protein 1 (AP-1)-dependent reporter expression caused by Ca(2+) ionophore or hypoxia. K252a also significantly decreased hypoxia-induced VEGF and NDRG-1/Cap43 gene expression in both human and mouse cells. Using a set of deletion VEGF-Luc promoter constructs, we found that both HIF-1 and two AP-1 sites contribute to hypoxia-mediated induction of transcription. In contrast, only AP-1 sites contributed to Ca(2+)-mediated VEGF-Luc induction. A dominant-negative AP-1 prevented Ca(2+)-dependent transcription and partially impaired hypoxia-mediated transcription. In addition, dominant-negative AP-1 diminished the expression of the NDRG-1/Cap43 gene following hypoxia. We conclude that during hypoxia, an increase in intracellular Ca(2+) activates a HIF-1-independent signaling pathway that involves AP-1-dependent transcription. Cooperation between the HIF-1 and AP-1 pathways allows fine regulation of gene expression during hypoxia.

• Authors: Konstantin Salnikow, Thomas Kluz, Max Costa, David Piquemal, Zoya N Demidenko, Keping Xie, Mikhail V Blagosklonny
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 22 Issue 6 Pg. 1734-41 (Mar 2002) ISSN: 0270-7306 [Print] United States
• PMID: 11865053 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cell Cycle Proteins
• DNA-Binding Proteins
• Endothelial Growth Factors
• HIF1A protein, human
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Intracellular Signaling Peptides and Proteins
• Ionophores
• Lymphokines
• N-myc downstream-regulated gene 1 protein
• NFATC Transcription Factors
• Nuclear Proteins
• Proto-Oncogene Proteins c-jun
• Transcription Factor AP-1
• Transcription Factors
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors
• Calcium

Topics

• Animals
• Calcium (metabolism, pharmacology)
• Cell Cycle Proteins (metabolism)
• Cell Hypoxia (physiology)
• Cell Line
• Cell Nucleus (metabolism)
• DNA-Binding Proteins (metabolism)
• Endothelial Growth Factors (genetics)
• Fibroblasts (cytology, metabolism)
• Gene Expression Regulation (drug effects, physiology)
• Genes, Dominant
• Humans
• Hypoxia-Inducible Factor 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Intracellular Fluid (metabolism)
• Intracellular Signaling Peptides and Proteins
• Ionophores (pharmacology)
• Lymphokines (genetics)
• Mice
• NFATC Transcription Factors
• Nuclear Proteins (metabolism)
• Promoter Regions, Genetic (physiology)
• Proto-Oncogene Proteins c-jun (metabolism)
• Transcription Factor AP-1 (genetics, metabolism)
• Transcription Factors (metabolism)
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors