Phospholipase D2 promotes degradation of hypoxia-inducible factor-1alpha independent of lipase activity
Experimental & Molecular Medicine
; : e196-2015.
Article
em En
| WPRIM
| ID: wpr-55052
Biblioteca responsável:
WPRO
ABSTRACT
Hypoxia-inducible factor-1alpha (HIF-1alpha) 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-1alpha 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-1alpha for ubiquitination and degradation. Here, we demonstrate that PLD2 protein itself interacts with HIF-1alpha, prolyl hydroxylase (PHD) and VHL to promote degradation of HIF-1alpha via the proteasomal pathway independent of lipase activity. PLD2 increases PHD2-mediated hydroxylation of HIF-1alpha by increasing the interaction of HIF-1alpha with PHD2. Moreover, PLD2 promotes VHL-dependent HIF-1alpha degradation by accelerating the association between VHL and HIF-1alpha. The interaction of the pleckstrin homology domain of PLD2 with HIF-1alpha also promoted degradation of HIF-1alpha and decreased expression of its target genes. These results indicate that PLD2 negatively regulates the stability of HIF-1alpha through the dynamic assembly of HIF-1alpha, PHD2 and VHL.
Texto completo:
1
Índice:
WPRIM
Assunto principal:
Fosfolipase D
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Linhagem Celular
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Ubiquitina-Proteína Ligases
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Complexo de Endopeptidases do Proteassoma
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Proteína Supressora de Tumor Von Hippel-Lindau
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Subunidade alfa do Fator 1 Induzível por Hipóxia
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Células HEK293
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Proteólise
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Mapas de Interação de Proteínas
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Prolil Hidroxilases
Limite:
Humans
Idioma:
En
Revista:
Experimental & Molecular Medicine
Ano de publicação:
2015
Tipo de documento:
Article