Phospholipase D1 protein coordinates dynamic assembly of HIF-1α-PHD-VHL to regulate HIF-1α stability

Mi Hee Park, Kang Yell Choi, Yunjin Jung, Do Sik Min

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Hypoxia-inducible factor-1α (HIF-1α) is a master transcriptional regulator of cellular response to hypoxia. In normoxia, HIF-1α is degraded through the prolyl hydroxylase (PHD) and von Hippel-Lindau (VHL) ubiquitination pathway. However, it is unknown whether PHD and VHL exert their enzymatic activities on HIF-1α separately or as a multiprotein complex. Here, we show that phospholipase D1 (PLD1) protein itself acts as a molecular platform, interacting directly with HIF-1α, PHD, and VHL, thereby dynamically assembling a multiprotein complex that mediates efficient degradation of HIF-1α in an O 2 -dependent manner. PLD1 depletion prevents degradation of HIF-1α however, overall, PLD1 activity is predominantly involved in the upregulation of HIF-1α through increased translation, despite negative regulation of HIF-1α stability by PLD1 protein itself, suggesting dual roles of PLD1 in the regulation of HIF-1α. Disruption of the interactions of PLD1 with the proteins might be involved in hypoxic stabilization of HIF-1α. Interestingly, the pleckstrin homology domain interacting with these proteins promoted degradation of HIF-1α independent of oxygen concentration and suppressed tumor progression. These observations define a novel function of PLD1 as a previously unrecognized HIF-1α regulator.

Original languageEnglish
Pages (from-to)11857-11872
Number of pages16
JournalOncotarget
Volume5
Issue number23
DOIs
Publication statusPublished - 2014 Jan 1

Fingerprint

Hypoxia-Inducible Factor-Proline Dioxygenases
Hypoxia-Inducible Factor 1
Proteins
Prolyl Hydroxylases
Multiprotein Complexes
phospholipase D1
Ubiquitination

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

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abstract = "Hypoxia-inducible factor-1α (HIF-1α) is a master transcriptional regulator of cellular response to hypoxia. In normoxia, HIF-1α is degraded through the prolyl hydroxylase (PHD) and von Hippel-Lindau (VHL) ubiquitination pathway. However, it is unknown whether PHD and VHL exert their enzymatic activities on HIF-1α separately or as a multiprotein complex. Here, we show that phospholipase D1 (PLD1) protein itself acts as a molecular platform, interacting directly with HIF-1α, PHD, and VHL, thereby dynamically assembling a multiprotein complex that mediates efficient degradation of HIF-1α in an O 2 -dependent manner. PLD1 depletion prevents degradation of HIF-1α however, overall, PLD1 activity is predominantly involved in the upregulation of HIF-1α through increased translation, despite negative regulation of HIF-1α stability by PLD1 protein itself, suggesting dual roles of PLD1 in the regulation of HIF-1α. Disruption of the interactions of PLD1 with the proteins might be involved in hypoxic stabilization of HIF-1α. Interestingly, the pleckstrin homology domain interacting with these proteins promoted degradation of HIF-1α independent of oxygen concentration and suppressed tumor progression. These observations define a novel function of PLD1 as a previously unrecognized HIF-1α regulator.",
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Phospholipase D1 protein coordinates dynamic assembly of HIF-1α-PHD-VHL to regulate HIF-1α stability. / Park, Mi Hee; Choi, Kang Yell; Jung, Yunjin; Min, Do Sik.

In: Oncotarget, Vol. 5, No. 23, 01.01.2014, p. 11857-11872.

Research output: Contribution to journalArticle

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