Protein Kinase C ζ Transactivates Hypoxia-Inducible Factor α by Promoting Its Association with p300 in Renal Cancer

Abstract

Hydroxylation at an asparagine residue at the COOH-terminal activation domain of hypoxia-inducible factor (HIF)-1/2 αs is essential for its inactivation under normoxic condition. To date, the mechanism by which HIF-α avoids the inhibitory effect of asparagine hydroxylase in renal cell carcinoma (RCC) in normoxia is undefined. We have shown herein that protein kinase C (PKC) ζ has an important role in HIF-α activation in RCC. By using dominant negative mutant and small interference RNA approaches, we have demonstrated that the association between HIF-α and p300 is modulated by PKCζ. Moreover, a novel signaling pathway involving phosphatidylinositol 3′-kinase and PKCζ has been shown to be responsible for the activation of HIF-α by inhibiting the mRNA expression of FIH-1 (factor inhibiting HIF-1) in RCC and thereby promoting the transcription of hypoxia-inducible genes such as vascular permeability factor/vascular endothelial growth factor.