Protein kinase C zeta transactivates hypoxia-inducible factor alpha by promoting its association with p300 in renal cancer.
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.
Datta
Kaustubh
K
Departmens of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Li
Jinping
J
Bhattacharya
Resham
R
Gasparian
Levon
L
Wang
Enfeng
E
Mukhopadhyay
Debabrata
D
D000123:Acetyltransferases / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000473:pathology; D008156:Luciferases / Q000235:genetics; D011493:Protein Kinase C / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D050880:p300-CBP Transcription Factors; D000099221:Protein Kinase C zeta; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D017931:DNA Primers; D051548:Histone Acetyltransferases; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008156:Luciferases; D011493:Protein Kinase C; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099221:Protein Kinase C zeta; D000099224:p300-CBP-Associated Factor; C497442:HIF1A protein, human