Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation

Masson, Norma; Willam, Carsten; Maxwell, Patrick H.; Pugh, Christopher W.; Ratcliffe, Peter J.

doi:10.1093/emboj/20.18.5197

Cited by 940 publications

(654 citation statements)

References 35 publications

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“…The abundance of HIF-1a subunits is mainly regulated by the rate of degradation. Oxygen-dependent hydroxylation at two proline residues (Pro402 and Pro564) of human HIF-1a mediates its interactions with a ubiquitin ligase (E3), von HippeleLindau (VHL), which targets HIF1a for proteasomal degradation (Ivan et al, 2001;Jaakkola et al, 2001), and contributes to the extremely rapid proteolysis of HIF-1a in cells under normoxia conditions (Masson et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells

Fernandes¹,

Guo²,

Zhang³

et al. 2006

Experimental Eye Research

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As in many other types of cells, retinal pigment epithelial (RPE) cells have an active ubiquitineproteasome pathway (UPP). However, the function of the UPP in RPE remains to be elucidated. The objective of this study is to determine the role of the UPP in controlling the levels and activities of transcription factors hypoxia-inducible factor (HIF) and NF-kB. We inhibited the UPP with proteasome-specific inhibitors and determined the activation of HIF and NF-kB as well as the expression and secretion of pro-angiogenic factors. HIF-1a was not detectable in ARPE-19 cells under normal culture conditions. However, when proteasome activity was inhibited, HIF-1a accumulated in RPE in a time-dependent manner. Consistent with accumulation of HIF-1a in the cells, levels of mRNA for vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) in RPE were up to 7-fold higher upon inhibition of the proteasome. Proteasome inhibition was also associated with a 2-fold increase in levels of mRNA for angiopoietin-1 (Ang-1). ARPE-19 cells secrete significant levels of VEGF under normal culture conditions. Inhibition of proteasome activity increased the secretion of VEGF by 2-fold. In contrast to the increase in HIF activity, NF-kB activation was reduced by proteasome inhibition. In addition, the expression and secretion of monocyte chemoattractant protein-1 (MCP-1) by RPE were substantially attenuated by the inhibition of proteasome activity. These data demonstrate that the UPP plays an important role in modulating the activities of HIF and NF-kB in the RPE. Consequences of an impairment of the UPP include accumulation of HIF-1a and diminished NF-kB activation, which lead to enhanced expression and secretion of pro-angiogenic factors and attenuated expression of MCP-1. Taken together, these data predict that the impairment of the UPP could lead to the development of AMD-related phenotypes.

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Section: Introductionmentioning

confidence: 99%

Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells

Fernandes¹,

Guo²,

Zhang³

et al. 2006

Experimental Eye Research

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“…7,20 This pVHL-HIF-a interaction is highly conserved between species, requires iron-and oxygen-dependent hydroxylation of specific proline residues (Pro402 and Pro564 in human HIF-1a; Pro405 and Pro531 in human HIF-2a) within the oxygen-dependent degradation domain of HIF-a and is necessary for the execution of HIF proteolysis under normoxia. [21][22][23][24][25][26][27] Therefore, absence of pVHL results in HIF-a stabilization, increased HIF transcriptional activity and upregulation of HIF target genes, such as vascular endothelial growth factor (VEGF), glucose transporter 1 and erythropoietin (EPO) irrespective of oxygen levels.To understand the role of pVHL-mediated HIF proteolysis in normal tissue physiology, tumorigenesis and during development, we have used cell-type-specific gene targeting based on Cre recombinase (Cre)/loxP-mediated recombination. In this review, we will summarize the findings from a variety of developmental and physiological studies in conditional VHL and HIF knockout mice and provide insights into the biological function of individual HIF transcription factors in a VHLdeficient background.…”

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confidence: 99%

The VHL tumor suppressor and HIF: insights from genetic studies in mice

2008

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The von Hippel-Lindau tumor suppressor gene product, pVHL, functions as the substrate recognition component of an E3-ubiquitin ligase, which targets the oxygen-sensitive a-subunit of hypoxia-inducible factor (HIF) for rapid proteasomal degradation under normoxic conditions and as such plays a central role in molecular oxygen sensing. Mutations in pVHL can be found in familial and sporadic clear cell carcinomas of the kidney, hemangioblastomas of the retina and central nervous system, and pheochromocytomas, underscoring its gatekeeper function in the pathogenesis of these tumors. Tissue-specific gene targeting of VHL in mice has demonstrated that efficient execution of pVHL-mediated HIF proteolysis under normoxia is fundamentally important for survival, proliferation, differentiation and normal physiology of many cell types, and has provided novel insights into the biological function of individual HIF transcription factors. In this review, we discuss the role of HIF in the development of the VHL phenotype. Germ-line mutations in the von Hippel-Lindau tumor (VHL) suppressor can be found in patients with VHL disease, a rare familial tumor syndrome characterized by the development of highly vascularized tumors in multiple organs. Major clinical manifestations of VHL disease include hemangioblastomas of the retina and central nervous system (CNS), renal cysts and renal cell carcinoma of the clear cell type (CC-RCC), pancreatic cysts and tumors, as well as pheochromocytomas. 1 The VHL tumor suppressor is also mutated in the majority of sporadic CC-RCCs, 2 highlighting its critical and central role in the regulation of cell growth and differentiation of epithelial kidney cells. Although the molecular function of the VHL gene product, pVHL, was initially not known when it was first identified by positional cloning in 1993, 3 observations that oxygen-dependent regulation of hypoxia-inducible genes was lost in VHL-deficient cell lines suggested a role for pVHL in oxygen sensing. [4][5][6] In a seminal paper, Maxwell et al. 7 showed that pVHL was critical for targeting the a-subunit of hypoxia-inducible factor (HIF) for oxygen-dependent proteolysis, thus providing a direct molecular link between VHLassociated tumorigenesis and oxygen sensing via HIF. HIFs belong to the PAS (Per-arylhydrocarbon receptor nuclear translocator (ARNT)-Sim) family of basic helix-loop-helix (bHLH) transcription factors and bind DNA as heterodimers. They consist of an oxygen-sensitive a-subunit and a constitutively expressed b-subunit, also known as ARNT or HIF-b. pVHL associates with the elongins B and C, cullin2 and Rbx [8][9][10][11][12] and functions as the substrate recognition component of an E3-ubiquitin ligase that ubiquitylates HIF-a. [13][14][15][16][17][18][19] All three HIF a-subunits, HIF-1a, HIF-2a and HIF-3a interact with pVHL. 7,20 This pVHL-HIF-a interaction is highly conserved between species, requires iron-and oxygen-dependent hydroxylation of specific proline residues (Pro402 and Pro564 in human HIF-1a; Pro405 and Pro531 in ...

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“…Under normoxic conditions, HIF-1α is hydroxylated by prolyl hydroxylases (PHDs) on specific proline residues localized within an oxygen-dependent degradation domain (ODDD) and by Factor inhibiting HIF-1 (FIH-1) on an asparagine residue in the C-terminal transactivation domain (C-TAD) [Masson et al, 2001;Epstein et al, 2001;Lando et al, 2002]. Von Hippel Lindau protein (pVHL) recognizes the prolyl hydroxylated form of HIF-1α…”

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confidence: 99%

Role of the HBx oncoprotein in carbonic anhydrase 9 induction

Holotnakova¹,

Tylková²,

Takáčová³

et al. 2009

Journal of Medical Virology

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International audienceCarbonic anhydrase 9 (CA9), as one of the most hypoxia-responsive genes, has been associated almost exclusively with hypoxic tumours. Its principal role is in pH regulation which helps tumour cells overcome intracellular acidosis and survive extended periods of time with low oxygen. Hypoxia-inducible factor 1 (HIF-1) is the main transcriptional activator of CA9. Hepatitis B virus X protein (HBx) has been shown to increase the transcriptional activity of HIF-1. HBx is often expressed from the gene integrated in the hepatocytes infected persistently and contributes significantly to alterations in host gene expression that can lead to the development of hepatocellular carcinoma (HCC) associated with HBV. The aim of this study was to determine the effect of HBx on expression of CA9. Transient transfection of HBx led to an increase in the expression of CA9 as assessed by RT-PCR and Western blotting. HBx was able to increase CA9 promoter activity significantly in several cell lines. The effect was mediated via HIF-1 and a functional HRE element located –10/–3 bp upstream of the CA9 transcription initiation site. These data suggest that CA9 may be involved in the development of HCC by contributing to the survival of hepatocytes infected with HBV in liver tissue with fibrosis

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Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylation

Cited by 940 publications

References 35 publications

Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells

Proteasome-dependent regulation of signal transduction in retinal pigment epithelial cells

The VHL tumor suppressor and HIF: insights from genetic studies in mice

Role of the HBx oncoprotein in carbonic anhydrase 9 induction

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