Protein kinase C-mediated modulation of FIH-1 expression by the homeodomain protein CDP/Cut/Cux

Jinping Li, Enfeng Wang, Shamit Dutta, Julie S. Lau, Shi Wen Jiang, Kaustubh Datta, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Under normoxia, FIH-1 (factor inhibiting HIF-1) inhibits the transcriptional activity of hypoxia-inducible factor (HIF); however, under such conditions, we observed a significant level of HIF activity in renal cell carcinoma (RCC). This phenomenon could be attributed to a decrease in the level of functional FIH that has been identified in our previous work. Nonetheless, the molecular mechanism of FIH regulation in cancer, in particular RCC, was unclear until now. In this communication, we have demonstrated that in RCC, the Cut-like homeodomain protein (CDP/Cut) is involved in FIH transcriptional regulation and is controlled by a specific signaling event involving protein kinase C (PKC) ζ. Furthermore, we have defined a unique CDP/Cut binding site on the FIH promoter. With chromatin immunoprecipitation assays, we show that CDP binds to the FIH-1 promoter in vivo and that this binding is PKC ζ dependent. Moreover, we have also defined a potential phosphorylation site in CDP (serine 987) that modulates FIH expression. CDP/Cut is a transcriptional repressor that decreases FIH-1 expression and subsequently leads to a decrease in the repressor activity of FIH-1. Without this repression, HIF activity increases, allowing for the increased transcription of the genes it regulates, such as the vascular endothelial growth factor and GLUT-1 genes. Both CDP and HIF levels are increased in several cancers and are responsible for the metastatic progression of the tumors. Taken together, our results suggest for the first time a potential connection between CDP and FIH that could lead to the development of future therapeutic interventions.

Original languageEnglish (US)
Pages (from-to)7345-7353
Number of pages9
JournalMolecular and cellular biology
Volume27
Issue number20
DOIs
StatePublished - Oct 1 2007

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Cytidine Diphosphate
Homeodomain Proteins
Protein Kinase C
Renal Cell Carcinoma
Hypoxia-Inducible Factor 1
Neoplasms
Chromatin Immunoprecipitation
Serine
Vascular Endothelial Growth Factor A
Genes
Carrier Proteins
Binding Sites
Phosphorylation
Hypoxia

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Protein kinase C-mediated modulation of FIH-1 expression by the homeodomain protein CDP/Cut/Cux. / Li, Jinping; Wang, Enfeng; Dutta, Shamit; Lau, Julie S.; Jiang, Shi Wen; Datta, Kaustubh; Mukhopadhyay, Debabrata.

In: Molecular and cellular biology, Vol. 27, No. 20, 01.10.2007, p. 7345-7353.

Research output: Contribution to journalArticle

Li, Jinping ; Wang, Enfeng ; Dutta, Shamit ; Lau, Julie S. ; Jiang, Shi Wen ; Datta, Kaustubh ; Mukhopadhyay, Debabrata. / Protein kinase C-mediated modulation of FIH-1 expression by the homeodomain protein CDP/Cut/Cux. In: Molecular and cellular biology. 2007 ; Vol. 27, No. 20. pp. 7345-7353.
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