Hypoxia-inducible Factor 1α (HIF-1α) Protein Is Rapidly Degraded by the Ubiquitin-Proteasome System under Normoxic Conditions

Salceda, Susana Alicia; Caro, Jaime

doi:10.1074/jbc.272.36.22642

Cited by 1,514 publications

(1,073 citation statements)

References 30 publications

Supporting

Mentioning

1,024

Contrasting

Unclassified

Order By: Relevance

“…In other types of cells, the levels of HIF-1a are mainly regulated by oxygen-dependent and UPP-mediated degradation (Salceda and Caro, 1997;Semenza, 2003;Hagg and Wennstrom, 2005). The current work demonstrates that HIF-1a in RPE is also regulated in an UPP-dependent manner.…”

Section: Discussionsupporting

confidence: 52%

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

Fernandes¹,

Guo²,

Zhang³

et al. 2006

Experimental Eye Research

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 52%

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

Fernandes¹,

Guo²,

Zhang³

et al. 2006

Experimental Eye Research

View full text Add to dashboard Cite

show abstract

“…Under normoxia, the HIF-1α subunit is rapidly degraded by the ubiquitin-proteasome system, thus hampering the heterodimeric HIF-1 activity [10]. By contrast, under hypoxia or in the presence of iron chelators, the degradation of HIF-1α is prevented [7,11,12]. As a result, this stabilization initiates a multi-step pathway of activation of HIF-1α that includes hypoxia-dependent nuclear translocation and dimerization with ARNT to interact with hypoxia responwww.cell-research.com | Cell Research Qi Fang Li et al 549 npg sive element (HRE) of target genes such as erythropoietin (EPO) [13], vascular endothelial growth factor (VEGF) [14], inducible nitric-oxide synthase [15], heme oxygenase 1 [16], and so on.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia upregulates hypoxia inducible factor (HIF)-3α expression in lung epithelial cells: characterization and comparison with HIF-1α

et al. 2006

View full text Add to dashboard Cite

The role of the hypoxia-inducible factor (HIF) subunits 1α and 2α in response to hypoxia is well established in lung epithelial cells, whereas little is known about HIF-3α with respect to transcriptional and translational regulation by hypoxia. HIF-3α and HIF-1α are two similar but distinct basic helix-loop-helix-PAS proteins, which have been postulated to activate hypoxia responsive genes in response to hypoxia. Here, we used quantitative real time RT-PCR and immunoblotting to determine the activation of HIF-3α vs. HIF-1α by hypoxia. HIF-3α was strongly induced by hypoxia (1% O 2 ) both at the level of protein and mRNA due to an increase in protein stability and transcriptional activation, whereas HIF-1α protein and mRNA levels enhanced transiently and then decreased because of a reduction in its mRNA stability in A549 cells, as measured on mRNA and protein levels. Interestingly, HIF-3α and HIF-1α exhibited strikingly similar responses to a variety of activating or inhibitory pharmacological agents. These results demonstrate that HIF-3α is expressed abundantly in lung epithelial cells, and that the transcriptional induction of HIF-3α plays an important role in the response to hypoxia in vitro. Our findings suggest that HIF-3α, as a member of the HIF system, is complementary rather than redundant to HIF-1α induction in protection against hypoxic damage in alveolar epithelial cells.

show abstract

“…4 The degradation of HIF1R is regulated in part by PHD enzymes, which hydroxylate HIF1R proline residues 564 and 402, thereby enabling binding to the von Hippel-Lindau protein and subsequent proteasomic degradation. 5 Under a sufficiently low partial pressure of oxygen, the rate of PHD-mediated hydroxylation of HIF1R is lessened such that the production of HIF1R outpaces its degradation. The accumulated HIF1R then translocates to the nucleus, leading to the formation of a HIF1R-HIF1β heterodimer and the activation of genes involved in hypoxic responses such as erythropoietin (epo) secretion and erythropoiesis, anaerobic glycolysis, and angiogenesis.…”

mentioning

confidence: 99%

Benzimidazole-2-pyrazole HIF Prolyl 4-Hydroxylase Inhibitors as Oral Erythropoietin Secretagogues

Rosen

Venkatesan

Peltier

et al. 2010

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

show abstract

Hypoxia-inducible Factor 1α (HIF-1α) Protein Is Rapidly Degraded by the Ubiquitin-Proteasome System under Normoxic Conditions

Cited by 1,514 publications

References 30 publications

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

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

Hypoxia upregulates hypoxia inducible factor (HIF)-3α expression in lung epithelial cells: characterization and comparison with HIF-1α

Benzimidazole-2-pyrazole HIF Prolyl 4-Hydroxylase Inhibitors as Oral Erythropoietin Secretagogues

Contact Info

Product

Resources

About