Role for casein kinase 2 in the regulation of HIF-1 activity.

Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that plays a major role in cellular adaptation to hypoxia. The mechanisms regulating HIF-1 activity occurs at multiple levels in vivo. The HIF-1alpha subunit is highly sensible to oxygen and is rapidly degraded by the proteasome 26S in normoxia. Activation in hypoxia occurs through a multistep process including inhibition of HIF-1alpha degradation, but also increase in the transactivation activity of HIF-1. Several data indicate that phosphorylation could play a role in this regulation. In this report, we investigated the role of casein kinase 2 (CK2), an ubiquitous serine/threonine kinase, in the regulation of HIF-1 activity. Hypoxia was capable of increasing the expression of the beta subunit of CK2, of inducing a relocalization of this subunit at the plasma membrane, of inducing nuclear translocation of the alpha subunit and of increasing CK2 activity. Three inhibitors of this kinase, DRB (5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole), TBB (4,5,6,7-tetrabromotriazole) and apigenin, as well as overexpression of a partial dominant negative mutant of CK2alpha, were shown to inhibit HIF-1 activity as measured by a reporter assay and through hypoxia-induced VEGF and aldolase expression. This does not occur at the stabilization process since they did not affect HIF-1alpha protein level. DNA-binding activity was also not inhibited. We conclude that CK2 is an important regulator of HIF-1 transcriptional activity but the mechanism of this regulation remains to be determined. Since HIF-1 plays a major role in tumor angiogenesis and since CK2 has been described to be overexpressed in tumor cells, this new pathway of regulation can be one more way for tumor cells to survive. Copyright 2005 Wiley-Liss, Inc