Cobalt Inhibits the Interaction between Hypoxia-inducible Factor-α and von Hippel-Lindau Protein by Direct Binding to Hypoxia-inducible Factor-α

Clear cell renal cell carcinoma (ccRCC) is characterized by loss of tumor suppressor Von Hippel Lindau (VHL) function, which leads to accumulation of hypoxia inducible factor α (including HIF1α and HIF2α). HIF2α was previously reported to be one of the major oncogenic drivers in ccRCC, however, its therapeutic targets remain challenging. Here we performed a deubiquitinase (DUB) complementary DNA (cDNA) library binding screen and discovered that ubiquitin-specific peptidase 37 (USP37) is a DUB that binds HIF2α and promotes HIF2α deubiquitination. As a result, USP37 promotes HIF2α protein stability in an enzymatically dependent manner, and depletion of USP37 leads to HIF2α down-regulation in ccRCC. Functionally, USP37 depletion causes decreased cell proliferation measured by MTS, two-dimensional (2D) colony formation as well as three-dimensional (3D) anchorage- independent growth. USP37 is also essential for maintaining kidney tumorigenesis in an orthotopic xenograft model and its depletion leads to both decreased primary kidney tumorigenesis and spontaneous lung metastasis. Our results suggest that USP37 is a potential therapeutic target in ccRCC.

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Hypoxia Inducible Factor-α Binding and Ubiquitylation by the von Hippel-Lindau Tumor Suppressor Protein

Journal of Biological Chemistry ◽

10.1074/jbc.m002740200 ◽

2000 ◽

Vol 275 (33) ◽

pp. 25733-25741 ◽

Cited By ~ 710

Author(s):

Matthew E. Cockman ◽

Norma Masson ◽

David R. Mole ◽

Panu Jaakkola ◽

Gin-Wen Chang ◽

...

Keyword(s):

Tumor Suppressor ◽

Hypoxia Inducible Factor ◽

Tumor Suppressor Protein ◽

Von Hippel Lindau ◽

Factor Α

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The von Hippel-Lindau Protein pVHL Inhibits Ribosome Biogenesis and Protein Synthesis

Journal of Biological Chemistry ◽

10.1074/jbc.m113.455121 ◽

2013 ◽

Vol 288 (23) ◽

pp. 16588-16597 ◽

Cited By ~ 15

Author(s):

Wen-Ting Zhao ◽

Cheng-Fu Zhou ◽

Xue-Bing Li ◽

Yun-Fang Zhang ◽

Li Fan ◽

...

Keyword(s):

Protein Synthesis ◽

Tumor Suppressor ◽

Ribosome Biogenesis ◽

Hypoxia Inducible Factor ◽

Suppressor Gene ◽

Nuclear Retention ◽

Von Hippel Lindau ◽

Ubiquitin Ligase Complex ◽

Ribosomal Protein S3 ◽

Factor Α

pVHL, the product of von Hippel-Lindau (VHL) tumor suppressor gene, functions as the substrate recognition component of an E3-ubiquitin ligase complex that targets hypoxia inducible factor α (HIF-α) for ubiquitination and degradation. Besides HIF-α, pVHL also interacts with other proteins and has multiple functions. Here, we report that pVHL inhibits ribosome biogenesis and protein synthesis. We find that pVHL associates with the 40S ribosomal protein S3 (RPS3) but does not target it for destruction. Rather, the pVHL-RPS3 association interferes with the interaction between RPS3 and RPS2. Expression of pVHL also leads to nuclear retention of pre-40S ribosomal subunits, diminishing polysomes and 18S rRNA levels. We also demonstrate that pVHL suppresses both cap-dependent and cap-independent protein synthesis. Our findings unravel a novel function of pVHL and provide insight into the regulation of ribosome biogenesis by the tumor suppressor pVHL.

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The regulation, localization, and functions of oxygen-sensing prolyl hydroxylase PHD3

Biological Chemistry ◽

10.1515/hsz-2012-0330 ◽

2013 ◽

Vol 394 (4) ◽

pp. 449-457 ◽

Cited By ~ 22

Author(s):

Panu M. Jaakkola ◽

Krista Rantanen

Keyword(s):

Cell Survival ◽

Hypoxia Inducible Factor ◽

Oxygen Sensors ◽

Cell Type ◽

Low Oxygen ◽

Von Hippel Lindau ◽

Low Oxygen Tension ◽

Cellular Oxygen ◽

Domain Protein ◽

Factor Α

Abstract The prolyl 4-hydroxylase domain protein 3 (PHD3) belongs to 2-oxoglutarate and iron-dependent dioxygenases. Together with the two closest paralogues, PHD1 and PHD2, these enzymes have been identified as cellular oxygen sensors that can mark the hypoxia-inducible factor α (HIF-α) for von Hippel-Lindau protein-mediated proteasomal destruction. Although having overlapping functions with PHD1 and PHD2, PHD3 markedly differs from the two isoforms. PHD3 shows a different expression pattern and subcellular localization as well as activity under low oxygen tension. Moreover, it has the widest range of non-HIF targets underlying its diverse functions. The functions of PHD3 differ depending on the cell type and also partially on the microenvironmental conditions it is expressed at. Under normoxia, PHD3 has been shown to be proapoptotic, but under hypoxia, it can have cell survival or proliferation-supporting functions. Here we discuss the regulation, targets, and functions of PHD3.

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Parallel Regulation of von Hippel-Lindau Disease by pVHL-Mediated Degradation of B-Myb and Hypoxia-Inducible Factor α

Molecular and Cellular Biology ◽

10.1128/mcb.00067-16 ◽

2016 ◽

Vol 36 (12) ◽

pp. 1803-1817 ◽

Cited By ~ 10

Author(s):

Fumihiko Okumura ◽

Keiji Uematsu ◽

Stuart D. Byrne ◽

Mie Hirano ◽

Akiko Joo-Okumura ◽

...

Keyword(s):

Growth Factor ◽

Critical Role ◽

Control Cell ◽

Hypoxia Inducible Factor ◽

Suppressor Gene ◽

Protein Product ◽

Von Hippel Lindau ◽

Microarray Screening ◽

Factor Α ◽

Vhl Disease

pVHL, the protein product of the von Hippel-Lindau (VHL) tumor suppressor gene, is a ubiquitin ligase that targets hypoxia-inducible factor α (HIF-α) for proteasomal degradation. Although HIF-α activation is necessary for VHL disease pathogenesis, constitutive activation of HIF-α alone did not induce renal clear cell carcinomas and pheochromocytomas in mice, suggesting the involvement of an HIF-α-independent pathway in VHL pathogenesis. Here, we show that the transcription factor B-Myb is a pVHL substrate that is degraded via the ubiquitin-proteasome pathway and that vascular endothelial growth factor (VEGF)- and/or platelet-derived growth factor (PDGF)-dependent tyrosine 15 phosphorylation of B-Myb prevents its degradation. Mice injected with B-Myb knockdown 786-O cells developed dramatically larger tumors than those bearing control cell tumors. Microarray screening of B-Myb-regulated genes showed that the expression of HIF-α-dependent genes was not affected by B-Myb knockdown, indicating that B-Myb prevents HIF-α-dependent tumorigenesis through an HIF-α-independent pathway. These data indicate that the regulation of B-Myb by pVHL plays a critical role in VHL disease.

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Role of the VHL (von Hippel–Lindau) gene in renal cancer: a multifunctional tumour suppressor

Biochemical Society Transactions ◽

10.1042/bst0360472 ◽

2008 ◽

Vol 36 (3) ◽

pp. 472-478 ◽

Cited By ~ 45

Author(s):

Michelle J. Nyhan ◽

Gerald C. O'Sullivan ◽

Sharon L. McKenna

Keyword(s):

Target Genes ◽

Hypoxia Inducible Factor ◽

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Tumour Suppressor ◽

Current Evidence ◽

Von Hippel Lindau ◽

Ubiquitin Ligase Complex ◽

Protein Functions ◽

Factor Α

The VHL (von Hippel–Lindau) tumour-suppressor gene is inactivated in VHL disease and in sporadic cases of CCRCC [clear-cell RCC (renal cell carcinoma)]. pVHL (VHL protein) functions as part of an E3 ubiquitin ligase complex that targets proteins for proteasomal degradation. The best-characterized substrate is HIF-α (hypoxia-inducible factor-α). Loss of pVHL and subsequent up-regulation of HIF target genes has been attributed to the highly vascular nature of these neoplasms. However, pVHL does not just function as the executioner of HIF-α. Additional functions of pVHL that may be important in preventing CCRCC tumorigenesis have been identified, including primary cilium maintenance, assembly of the extracellular matrix and roles in the stabilization of p53 and Jade-1 (gene for apoptosis and differentiation in epithelia). Current evidence indicates that pVHL probably requires additional co-operating signalling pathways for CCRCC initiation and tumorigenesis.

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