Regulation of FIH Expression in Renal Cancer
The Tumor Angiogenesis and Vascular Biology Lab studies how hypoxia inducible factor-1/2 HIF-1/2 α (HIF-1/2α) regulates the expression of factor inhibitors for hypoxia (FIH) in renal cell carcinoma.
Hydroxylation at an asparagine residue at the C-terminal activation domain of HIF-1/2α is essential for its inactivation under normoxic conditions. The mechanism by which HIF-1/2α avoids the inhibitory effect of asparagine hydroxylase in renal cell carcinoma in normoxia is undefined.
However, Dr. Mukhopadhyay's lab has shown that protein kinase C zeta (PKC z) has an important role in HIF-1/2α activation in renal cell carcinoma.
By using a dominant-negative mutant and small interfering RNA (siRNA) approaches, the lab has demonstrated that the association between HIF-1/2α 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-1/2α by inhibiting the mRNA expression of FIH in renal cell carcinoma and thereby promoting the transcription of hypoxia inducible genes such as vascular permeability factor/vascular endothelial growth factor (VPF/VEGF).
Dr. Mukhopadhyay's lab is now working to understand the minimal promoter region of FIH that is responsible for FIH transcriptional activity in renal cancer.