Tumor Angiogenesis and Vascular Biology - Debabrata Mukhopadhyay

Regulation of FIH Expression in Renal Cancer

Hydroxylation at an asparagine residue at the C-terminal activation domain of hypoxia inducible factor-1/2 a s (HIF a ) is essential for its inactivation under normoxic condition. To date, the mechanism by which HIF a avoids the inhibitory effect of asparagine hydroxylase in renal cell carcinoma (RCC) in normoxia is undefined. We have shown herein that protein kinase C zeta (PKC z ) has an important role in HIF a activation in RCC.

By utilizing a dominant-negative mutant and siRNA approaches, we have demonstrated that the association between HIF a and p300 is modulated by PKC z . Moreover, a novel signaling pathway involving PI-3 kinase and PKC z has been shown to be responsible for the activation of HIF a by inhibiting the mRNA expression of Factor inhibitors for Hypoxia (FIH) in RCC and thereby promoting the transcription of hypoxia inducible genes like VPF/VEGF. Currently, we are trying to understand the minimal promoter region of FIH that is responsible for FIH transcriptional activity in renal cancer.