Oncotarget

Research Papers:

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

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

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Oncotarget. 2014; 5:11857-11872. https://doi.org/10.18632/oncotarget.2613

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Abstract

Mi Hee Park1, Kang-Yell Choi2,3, Yunjin Jung4 and Do Sik Min1,3

1 Department of Molecular Biology, Pusan National University, Busan, Republic of Korea

2 Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea

3 Translational Research Center for Protein Function Control, Yonsei University, Seoul, Republic of Korea

4 College of Pharmacy, Pusan National University, Busan, Republic of Korea

Correspondence:

Do Sik Min, email:

Keywords: Phospholipase D1, Hypoxia-inducible factor-1α, Prolyl hydroxylase, Von Hippel-Lindau, Pleckstrin homology domain

Received: July 16, 2014 Accepted: October 21, 2014 Published: October 21, 2014

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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