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PMID:25361009
| Citation |
'Park, MH, Choi, KY, Jung, Y and Min, DS (2014) Phospholipase D1 protein coordinates dynamic assembly of HIF-1α-PHD-VHL to regulate HIF-1α stability. Oncotarget ' |
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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 O2-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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Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
| GO:0045727: positive regulation of translation |
ECO:0000315: mutant phenotype evidence used in manual assertion |
P |
Figure S1A shows a decrease in translation of HIF-1alpha in cells transfected with PLD1 and also subject to a PLD1 inhibitor. Figure S1E shows a decrease in translation in cells transfected with a catalytically inactive mutant PLD1. |
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Notes
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References
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