Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL

Hon, Wai-Ching; Wilson, Michael; Harlos, K.; Claridge, Timothy D. W.; Schofield, Christopher J.; Pugh, Christopher W.; Maxwell, Patrick H.; Ratcliffe, Peter J.; Stuart, David I.; Jones, E Y

doi:10.1038/nature00767

Cited by 669 publications

(636 citation statements)

References 29 publications

Supporting

Mentioning

612

Contrasting

Unclassified

Order By: Relevance

“…This approach identified the HIF PHDs as the products of genes related to C.elegans egl-9, a gene that was first described in the context of an egg-laying abnormal phenotype [25]. In mammalian cells, three PHD isoforms were identified (PHD 1-3), and shown to hydroxylate HIF-α in vitro [26][27]. These enzymes have an absolute requirement for oxygen as the substrate.…”

Section: Hif Is Protective For Mucosal Inflammationmentioning

confidence: 99%

“…The overall reaction results in insertion of one oxygen atom into the HIF-α peptide substrate at the proline residue, with the other oxygen molecule generating succinate from 2-OG with the release of CO 2 . Reactions conducted in a limited oxygen environment have revealed that the activity of the purified enzyme is strikingly sensitive to diminished levels of oxygen in vitro [26][27]. The three enzymes have different tissue distributions and, at least under conditions of overexpression, have distinct patterns of subcellular localization [15,19].…”

Section: Hif Is Protective For Mucosal Inflammationmentioning

confidence: 99%

See 1 more Smart Citation

Hypoxia and gastrointestinal disease

2007

View full text Add to dashboard Cite

The gastrointestinal mucosa is a richly perfused vascular bed directly juxtaposed with the anaerobic and nonsterile lumen of the gut. As such, intestinal epithelial cells, which line the mucosa, experience a uniquely steep physiologic oxygen gradient in comparison with other cells of the body. Inflammation associated with a loss of epithelial barrier function and unregulated exposure of the mucosal immune system to luminal antigens leads to inflammatory bowel disease (IBD), a relatively common disorder with severe morbidity and a limited therapeutic repertoire. During IBD, increased tissue metabolism and vasculitis renders the chronically inflamed mucosa and particularly the epithelium hypoxic, giving rise to the activation of the hypoxia-responsive transcription factor hypoxia-inducible factor (HIF). Recent studies utilizing conditional intestinal epithelial hif1a-null mice have revealed a protective role for epithelial HIF-1α in murine models of IBD. Such protection occurs, at least in part, through HIF-dependent induction of barrier-protective genes in the epithelium. More recently, studies employing pharmacologic activation of HIF via inhibition of HIF prolyl hydroxylases revealed a profoundly protective effect of these agents in murine models of colitis. In this paper, we review this pathway in detail and examine the therapeutic potential for targeting HIF hydroxylases in intestinal mucosal inflammatory disease.

show abstract

Section: Hif Is Protective For Mucosal Inflammationmentioning

confidence: 99%

Section: Hif Is Protective For Mucosal Inflammationmentioning

confidence: 99%

Hypoxia and gastrointestinal disease

2007

View full text Add to dashboard Cite

show abstract

“…HIF-1 constitutes an oxygen-dependent a-subunit and a constitutively expressed b-subunit that interact through mutual basic helix-loop-helix domains [2]. HIF-1a oxygen-dependent domain undergoes site-specific proline hydroxylation by prolyl hydroxylases, which allows subsequent ubiquitination mediated by the von Hippel-Lindau protein [3][4][5]. In the absence of molecular oxygen, HIF-a hydroxylation is abrogated, leading to its cellular accumulation.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia controls CD4⁺CD25⁺ regulatory T‐cell homeostasis via hypoxia‐inducible factor‐1α

et al. 2008

View full text Add to dashboard Cite

Recent data suggest that hypoxia and its principal molecular signature HIF-1 (hypoxiainducing factor-1) may tune down inflammation by dictating anti-inflammatory programs. We tested the effects of hypoxia and HIF-1a on the homeostasis of naturally occurring regulatory T cells (Treg) and their transcriptional activator Foxp3. Hypoxia induced a timedependent increase in HIF-1a in mouse and human T cells. Hypoxia upregulated the expression of Foxp3 in Jurkat T cells, human and murine mononuclear cells. The effects of hypoxia on Foxp3 expression were HIF-1a-dependent as they were abolished upon transfection with short-interfering RNAs for HIF-1a and promoted by HIF-1a overexpression. Hypoxia increased the potency of Treg, as hypoxic CD4 1 CD25 1 lymphocytes were more effective than normoxic cells in suppressing the proliferation of CD4 1 CD25 À effectors. In vivo expression of HIF-1a achieved by hydrodynamic injection of the respective naked DNA similarly induced an increase in Foxp3 expression and an increase in the number of functionally active Foxp3 1 CD4 1 CD25 1 Treg. Thus, hypoxia dictates an antiinflammatory program by driving expression of HIF-1a that acts to increase the number and suppressive properties of naturally occurring CD4 1 CD25 1 Treg.Key words: Foxp3 Á HIF-1 Á Hypoxia Á Inflammation Á Regulatory T cells IntroductionUnder hypoxia, hypoxia-inducible factor-1 (HIF-1) plays a key role in controlling glycolysis, angiogenesis, erythropoiesis and cell survival [1]. HIF-1 constitutes an oxygen-dependent a-subunit and a constitutively expressed b-subunit that interact through mutual basic helix-loop-helix domains [2]. HIF-1a oxygen-dependent domain undergoes site-specific proline hydroxylation by prolyl hydroxylases, which allows subsequent ubiquitination mediated by the von Hippel-Lindau protein [3][4][5]. In the absence of molecular oxygen, HIF-a hydroxylation is abrogated, leading to its cellular accumulation. HIF subunits heterodimerize, and activate a wide range of target genes by binding to hypoxia response elements.T-lymphocytes that comprise a principal effector component of the cellular immune response are exposed to hypoxia in target microenvironments in which they are assumed to dictate inflammatory programs. Target sites include tumors and healthy organs that confront T cells with gradients of low oxygen tension. Recent literature suggests that blunted HIF-1a expression results in a net proinflammatory program evident by increased production inflammatory cytokines upon TCR engagement [6]. Similar results were obtained upon knocking out HIF-1 selectively in T cells [7]. Additionally, HIF-1a was reported to play an inhibitory role in the regulation of T-cell receptor signal transduction by controlling intracellular calcium balance [8]. Collectively, these observations suggest that HIF-1 drives a Th2 favored response by downregulated Th1 programs [9][10][11]. Naturally occurring CD4 1 CD25 1 regulatory T cells (Treg) comprise a relatively newly characterized population that has evolved to tune do...

show abstract

“…7 In its hydroxylated form HIF-1a is recognized by the von Hippel Lindau tumor suppressor protein and targeted for ubiquitination and subsequent proteasomal degradation. 8,9 Upon stabilization of HIF-1a and heterodimerization with HIF-1b, HIF-1 regulates the cellular and systemic response to environmental changes in oxygenation. In tumor tissue, the HIF-1-induced gene expression influences tumor growth and impairs tumor response to chemotherapy and radiotherapy.…”

mentioning

confidence: 99%

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

Wottawa

Leisering

Ahlen

et al. 2012

Intl Journal of Cancer

View full text Add to dashboard Cite

The prolyl-4-hydroxylase domain 1-3 (PHD1-3) enzymes are regulating the protein stability of the a-subunit of the hypoxiainducible factor-1 (HIF-1), which mediates oxygen-dependent gene expression. PHD2 is the main isoform regulating HIF-1a hydroxylation and thus stability in normoxia. In human cancers, HIF-1a is overexpressed as a result of intratumoral hypoxia which in turn promotes tumor progression. The role of PHD2 for tumor progression is in contrast far from being thoroughly understood. Therefore, we established PHD2 knockdown clones of MDA-MB-231 breast cancer cells and analyzed their tumorforming potential in a SCID mouse model. Tumor progression was significantly impaired in the PHD2 knockdown MDA-MB-231 cells, which could be partially rescued by re-establishing PHD2 expression. In a RNA profile screen, we identified the secreted phosphoprotein 1 (SPP1) as one target, which is differentially regulated as a consequence of the PHD2 knockdown. Knockdown of PHD2 drastically reduced the SPP1 expression in MDA-MB-231 cells. A correlation of SPP1 and PHD2 expression was additionally verified in 294 invasive breast cancer biopsies. In subsequent analyses, we identified that PHD2 alters the processing of transforming growth factor (TGF)-b1, which is highly involved in SPP1 expression. The altered processing capacity was associated with a dislocation of the pro-protein convertase furin. Thus, our data demonstrate that in MDA-MB-231 cells PHD2 might affect tumor-relevant TGF-b1 target gene expression by altering the TGF-b1 processing capacity.

show abstract

Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL

Cited by 669 publications

References 29 publications

Hypoxia and gastrointestinal disease

Hypoxia and gastrointestinal disease

Hypoxia controls CD4⁺CD25⁺ regulatory T‐cell homeostasis via hypoxia‐inducible factor‐1α

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

Contact Info

Product

Resources

About

Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL

Cited by 669 publications

References 29 publications

Hypoxia and gastrointestinal disease

Hypoxia and gastrointestinal disease

Hypoxia controls CD4+CD25+ regulatory T‐cell homeostasis via hypoxia‐inducible factor‐1α

Knockdown of prolyl‐4‐hydroxylase domain 2 inhibits tumor growth of human breast cancer MDA‐MB‐231 cells by affecting TGF‐β1 processing

Contact Info

Product

Resources

About

Hypoxia controls CD4⁺CD25⁺ regulatory T‐cell homeostasis via hypoxia‐inducible factor‐1α