Hypoxia induces PDK4 gene expression through induction of the orphan nuclear receptor ERRγ.

Autor: Ja Hee Lee, Eun-Jin Kim, Don-Kyu Kim, Ji-Min Lee, Seung Bum Park, In-Kyu Lee, Robert A Harris, Mi-Ock Lee, Hueng-Sik Choi
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Zdroj: PLoS ONE, Vol 7, Iss 9, p e46324 (2012)
Druh dokumentu: article
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0046324
Popis: Multiple cellular signaling pathways that control metabolism and survival are activated when cell are incubated under hypoxic conditions. Activation of the hypoxia inducible factor (HIF)-1 promotes expression of genes that increase the capacity to cope with the stress imposed by a reduced oxygen environment. Here we show that the orphan nuclear receptor estrogen related receptor γ (ERRγ) plays a critical role in hypoxia-mediated activation of pyruvate dehydrogenase kinase 4 (PDK4) gene expression. ERRγ mRNA and protein levels were increased by hypoxia or desferrioxamine (DFO) treatment in hepatoma cell lines. Co-expression of HIF-1α and β increased ERRγ promoter activity as well as mRNA expression, while knockdown of endogenous HIF-1α reduced the hypoxia-mediated induction of ERRγ. In addition, hypoxia also increased the promoter activity and mRNA level of PDK4 in HepG2 cells. Adenovirus mediated-overexpression of ERRγ specifically increased PDK4 gene expression, while ablation of endogenous ERRγ significantly decreased hypoxia-mediated induction of PDK4 gene expression. Finally, GSK5182, an inverse agonist of ERRγ, strongly inhibited the hypoxia-mediated induction of PDK4 protein and promoter activity. Regulation of the transcriptional activity of ERRγ may provide a therapeutic approach for the regulation of PDK4 gene expression under hypoxia.
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