Activation of HIF-prolyl Hydroxylases by R59949, an Inhibitor of the Diacylglycerol Kinase

Temes, Elisa; Martı́n-Puig, Silvia; Acosta‐Iborra, Bárbara; Castellanos, María C.; Feijóo-Cuaresma, Mónica; Olmos, Gemma; Aragonés, Julián; Landázuri, Manuel O.

doi:10.1074/jbc.m414694200

Cited by 56 publications

(52 citation statements)

References 55 publications

(30 reference statements)

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“…R59949 is a diacylglycerol kinase inhibitor and an activator of HIF prolyl hydroxylase (37), and as a consequence increases degradation of HIF-1␣ protein by a mechanism involving Von Hippel Lindau (VHL) protein. VHL protein is a component of E3 ubiquitin ligase complex that causes ubiquitinization and proteosome-dependent degradation of HIF-1␣ subunits.…”

Section: Discussionmentioning

confidence: 99%

A Novel Role of Hypoxia-Inducible Factor in Cobalt Chloride- and Hypoxia-Mediated Expression of IL-8 Chemokine in Human Endothelial Cells

Kim¹,

Rajagopal²,

Gonsalves³

et al. 2006

The Journal of Immunology

169

123

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Tissue hypoxemia is common in several pathological diseases, including vaso-occlusion in sickle cell disease and myocardial infarction. One finds increased presence of leukocytes during lung injury and at sites of inflammation in vascular endothelium. In this study, we used human pulmonary microvascular endothelial cells and human dermal microvascular endothelial immortalized cell line to delineate the cellular signaling mechanism of hypoxia- and CoCl2 (a mimetic of hypoxia)-induced IL-8 expression, and the latter’s role in chemotaxis of polmorphonuclear neutrophils. We show that hypoxia- and CoCl2-induced IL-8 mRNA and protein expression involved activation of PI3K/Akt and p38 MAPK, but not MEK kinase. Analysis of some transcription factors associated with IL-8 promoter revealed that hypoxia and CoCl2 increased DNA-binding activity of hypoxia-inducible factor-1α (HIF-1α), NF-κB, and AP-1. In addition, we show that hypoxia- and CoCl2-induced IL-8 expression requires activation of HIF as demonstrated by the following: 1) EMSA; 2) transfection studies with IL-8 promoter reporter constructs with mutation in HIF-1α binding site; 3) attenuation of IL-8 expression by both HIF-1α small interfering RNA and R59949; 4) augmentation of IL-8 expression by either transfection with HIF-prolyl hydroxylase-2 small interfering RNA or overexpression of HIF-1α; and 5) chromatin immunoprecipitation analysis. Moreover, conditioned medium from hypoxia-treated endothelial cells augmented chemotaxis of neutrophils, due to release of IL-8. These data indicate that hypoxia-induced signaling in vascular endothelium for transcriptional activation of IL-8 involves PI3K/Akt, p38 MAPK, and HIF-1α. Pharmacological agents, which inhibit HIF-1α, may possibly ameliorate inflammation associated with hypoxia in pathological diseases.

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Section: Discussionmentioning

confidence: 99%

A Novel Role of Hypoxia-Inducible Factor in Cobalt Chloride- and Hypoxia-Mediated Expression of IL-8 Chemokine in Human Endothelial Cells

Kim¹,

Rajagopal²,

Gonsalves³

et al. 2006

The Journal of Immunology

169

123

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“…2A. Hydroxylation at Pro 402 /Pro 564 seems to be an irreversible process (39,40) and increases pVHL affinity for HIF-1a by several orders of magnitude (17,18,45). This leads to further poly-ubiquitination, recruitment of transcriptional corepressors (histone deacetylases), and impaired HIF function (16).…”

Section: Discussionmentioning

confidence: 99%

Suppression of the Hypoxia-Inducible Factor-1 Response in Cervical Carcinoma Xenografts by Proteasome Inhibitors

Birle

Hedley

2007

Cancer Research

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Experimental data suggest therapeutic advantage from selective disruption of the hypoxia response. We recently found that the proteasome inhibitor bortezomib decreases tumor carbonic anhydrase IX (CAIX) expression in colon cancer patients and herein report a companion laboratory study to test if this effect was the result of hypoxia-inducible factor (HIF) inhibition. Human cervical (SiHa and Me180) and colon (RKO) carcinoma cell lines were treated with bortezomib or the structurally unrelated proteasome inhibitor MG132 in normoxic and hypoxic conditions in vitro. Two different in vivo experiments investigated bortezomib effects after single dose (2 mg/kg, 24 h) or longer exposure in severe combined immunodeficient mice bearing SiHa xenografts. Treatment with either drug produced accumulation of HIF-1A in vitro but strongly inhibited the production of CAIX and vascular endothelial growth factor (VEGF) under hypoxia. This correlated with more than 10-fold reduction in HIF-1 transcriptional activity under hypoxic conditions. A similar effect of bortezomib was seen in vivo, using the nitroimidazole probe EF5 to define regions of tumor hypoxia and a triple immunofluorescence technique to measure the spatial distributions of HIF-1A and CAIX. Plasma VEGF levels decreased by f90% during treatment with bortezomib, indicating that this agent can potently inhibit the hypoxia response in tumors. [Cancer Res 2007;67(4):1735-43]

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“…Some proteins, such as OS-9, the protein product of a widely expressed gene with unclear function, have been shown to promote prolyl hydroxylation by interacting with both HIF-1␣ and PHDs, thereby promoting the O 2 -dependent degradation of HIF-1␣ (Baek et al, 2005). In addition, several second messengers have also been shown to modify the activity of PHDs (Appelhoff et al, 2004;Hirota et al, 2004;Temes et al, 2005).…”

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confidence: 99%

Hypoxia-Inducible Factor-1 (HIF-1)

Costa²

2006

Mol Pharmacol

1,424

1,209

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Adaptation to low oxygen tension (hypoxia) in cells and tissues leads to the transcriptional induction of a series of genes that participate in angiogenesis, iron metabolism, glucose metabolism, and cell proliferation/survival. The primary factor mediating this response is the hypoxia-inducible factor-1 (HIF-1), an oxygen-sensitive transcriptional activator. HIF-1 consists of a constitutively expressed subunit HIF-1␤ and an oxygen-regulated subunit HIF-1␣ (or its paralogs HIF-2␣ and HIF-3␣). The stability and activity of the ␣ subunit of HIF are regulated by its post-translational modifications such as hydroxylation, ubiquitination, acetylation, and phosphorylation. In normoxia, hydroxylation of two proline residues and acetylation of a lysine residue at the oxygen-dependent degradation domain (ODDD) of HIF-1␣ trigger its association with pVHL E3 ligase complex, leading to HIF-1␣ degradation via ubiquitin-proteasome pathway. In hypoxia, the HIF-1␣ subunit becomes stable and interacts with coactivators such as cAMP response element-binding protein binding protein/p300 and regulates the expression of target genes. Overexpression of HIF-1 has been found in various cancers, and targeting HIF-1 could represent a novel approach to cancer therapy.The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key regulator responsible for the induction of genes that facilitate adaptation and survival of cells and the whole organism from normoxia (ϳ21% O 2 ) to hypoxia (ϳ1% O 2 ) (Wang et al., 1995;Semenza, 1998). Since the identification of HIF, 2 decades ago, our knowledge of it has grown exponentially. Because of the realization that hypoxia has a strong impact, via gene expression, on cell biology and mammalian physiology, there has been enormous growing interest in the biology of the HIF-1 pathway and its role in human diseases such as cancer. Therefore, this review considers what has been learned about HIF-1: its discovery, its regulation, its target gene, its role in development and disease, and its implication for therapy. The Discovery of HIF-1HIF-1␣. HIF-1 was discovered by the identification of a hypoxia response element (HRE; 5Ј-RCGTG-3Ј) in the 3Ј enhancer of the gene for erythropoietin (EPO), a hormone that stimulates erythrocyte proliferation and undergoes hypoxiainduced transcription (Goldberg et al., 1988;Semenza et al., 1991). Subsequent studies have revealed the protein that binds to the HRE under hypoxic conditions as HIF-1, a heterodimeric complex consisting of a hypoxically inducible subunit HIF-1␣ and a constitutively expressed subunit HIF-1␤ (Wang et al., 1995). HIF-1␤ is also known as the aryl hydrocarbon nuclear translocator (ARNT), which was originally identified as a binding partner of the aryl hydrocarbon receptor (Reyes et al., 1992), whereas HIF-1␣ was newly discovered. These proteins belong to the basic helix-loop-helixPer-ARNT-Sim (bHLH-PAS) protein family ( Fig. 1) (Wang et al., 1995). The bHLH and PAS motifs are required for heterodimer formation between the HIF-1␣ and HIF-1␤ ...

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Activation of HIF-prolyl Hydroxylases by R59949, an Inhibitor of the Diacylglycerol Kinase

Cited by 56 publications

References 55 publications

A Novel Role of Hypoxia-Inducible Factor in Cobalt Chloride- and Hypoxia-Mediated Expression of IL-8 Chemokine in Human Endothelial Cells

A Novel Role of Hypoxia-Inducible Factor in Cobalt Chloride- and Hypoxia-Mediated Expression of IL-8 Chemokine in Human Endothelial Cells

Suppression of the Hypoxia-Inducible Factor-1 Response in Cervical Carcinoma Xenografts by Proteasome Inhibitors

Hypoxia-Inducible Factor-1 (HIF-1)

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