KMID : 0620920150470110004
|
|
Experimental & Molecular Medicine 2015 Volume.47 No. 11 p.4 ~ p.4
|
|
Phospholipase D2 promotes degradation of hypoxia-inducible factor-1¥á independent of lipase activity
|
|
Park Mi-Hee
Bae Sun-Sik Choi Kang-Yell Min Do-Sik
|
|
Abstract
|
|
|
Hypoxia-inducible factor-1¥á (HIF-1¥á) 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-1¥á 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-1¥á for ubiquitination and degradation. Here, we demonstrate that PLD2 protein itself interacts with HIF-1¥á, prolyl hydroxylase (PHD) and VHL to promote degradation of HIF-1¥á via the proteasomal pathway independent of lipase activity. PLD2 increases PHD2-mediated hydroxylation of HIF-1¥á by increasing the interaction of HIF-1¥á with PHD2. Moreover, PLD2 promotes VHL-dependent HIF-1¥á degradation by accelerating the association between VHL and HIF-1¥á. The interaction of the pleckstrin homology domain of PLD2 with HIF-1¥á also promoted degradation of HIF-1¥á and decreased expression of its target genes. These results indicate that PLD2 negatively regulates the stability of HIF-1¥á through the dynamic assembly of HIF-1¥á, PHD2 and VHL.
|
|
KEYWORD
|
|
|
|
FullTexts / Linksout information
|
|
|
|
Listed journal information
|
|
|