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- 2015.1
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Hypoxia-inducible factor-1α (HIF-1α) is a key transcriptional mediator that coordinates the expression of various genes involved in tumorigenesis in response to changes in oxygen tension. The stability of HIF-1α protein is determined by oxygen-dependent prolyl hydroxylation, which is required for binding of the von Hippel-Lindau protein (VHL), the recognition component of an E3 ubiquitin ligase that targets HIF-1α for ubiquitination and degradation. Here, we demonstrate that PLD2 protein itself interacts with HIF-1α, prolyl hydroxylase (PHD) and VHL to promote degradation of HIF-1α via the proteasomal pathway independent of lipase activity. PLD2 increases PHD2-mediated hydroxylation of HIF-1α by increasing the interaction of HIF-1α with PHD2.
Moreover, PLD2 promotes VHL-dependent HIF-1α degradation by accelerating the association between VHL and HIF-1α. The interaction of the pleckstrin homology domain of PLD2 with HIF-1α also promoted degradation of HIF-1α and decreased expression of its target genes. These results indicate that PLD2 negatively regulates the stability of HIF-1α through the dynamic assembly of HIF-1α, PHD2 and VHL.
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참고문헌 (24)
참고문헌 신청
Bruntz RC / 2014 / Phospholipase D signaling pathways and phosphatidic acid as therapeutic targets in cancer / Pharmacol Rev 66 : 1033 ~ 1079
Chen Q / 2012 / Key roles for the lipid signaling enzyme phospholipase d1 in the tumor microenvironment during tumor angiogenesis and metastasis / Sci Signal 5 : ra79 ~
Colley WC / 1997 / Cloning and expression analysis of murine phospholipase D1 / Biochem J 326 : 745 ~ 753
Gomez-Cambronero J / 2012 / Biochemical and cellular implications of a dual lipase-GEF function of phospholipase D2 / J Leukoc Biol 92 : 461 ~ 467
Gomez-Cambronero J. / 2014 / Phospholipase D in cell signaling : from a myriad of cell functions to cancer growth and metastasis / J Biol Chem 286 : 22557 ~ 22566
Chen Q / 2012 / Key roles for the lipid signaling enzyme phospholipase d1 in the tumor microenvironment during tumor angiogenesis and metastasis / Sci Signal 5 : ra79 ~
Colley WC / 1997 / Cloning and expression analysis of murine phospholipase D1 / Biochem J 326 : 745 ~ 753
Gomez-Cambronero J / 2012 / Biochemical and cellular implications of a dual lipase-GEF function of phospholipase D2 / J Leukoc Biol 92 : 461 ~ 467
Gomez-Cambronero J. / 2014 / Phospholipase D in cell signaling : from a myriad of cell functions to cancer growth and metastasis / J Biol Chem 286 : 22557 ~ 22566
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