Protein kinase C zeta transactivates hypoxia-inducible factor alpha by promoting its association with p300 in renal cancer

Cancer Res. 2004 Jan 15;64(2):456-62. doi: 10.1158/0008-5472.can-03-2706.

Abstract

Hydroxylation at an asparagine residue at the COOH-terminal activation domain of hypoxia-inducible factor (HIF)-1/2 alphas is essential for its inactivation under normoxic condition. To date, the mechanism by which HIF-alpha 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) zeta has an important role in HIF-alpha activation in RCC. By using dominant negative mutant and small interference RNA approaches, we have demonstrated that the association between HIF-alpha and p300 is modulated by PKCzeta. Moreover, a novel signaling pathway involving phosphatidylinositol 3'-kinase and PKCzeta has been shown to be responsible for the activation of HIF-alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetyltransferases / metabolism
  • Carcinoma, Renal Cell / enzymology*
  • Carcinoma, Renal Cell / pathology
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • DNA Primers
  • Gene Expression Regulation, Neoplastic
  • Histone Acetyltransferases
  • Humans
  • Hydroxylation
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Kidney Neoplasms / enzymology*
  • Kidney Neoplasms / pathology
  • Luciferases / genetics
  • Protein Kinase C / genetics*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • p300-CBP Transcription Factors

Substances

  • Cell Cycle Proteins
  • DNA Primers
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Messenger
  • RNA, Small Interfering
  • Transcription Factors
  • Luciferases
  • Acetyltransferases
  • Histone Acetyltransferases
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • protein kinase C zeta
  • Protein Kinase C