Hypoxic transcription gene profiles under the modulation of nitric oxide in nuclear run on-microarray and proteomics

Igwe, Emeka I.; Essler, Silke; Al-Furoukh, Natalie; Dehne, Nathalie; Brüne, Bernhard

doi:10.1186/1471-2164-10-408

Cited by 25 publications

(22 citation statements)

References 51 publications

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“…SCD1 is one of the target genes upregulated under hypoxic stress . In our study, using the human VHL‐deficient RCC line 786‐0, which has constitutively expressed HLF‐2α and gives a model to investigate the effects of HLF‐2α on its target genes, we found that SCD1 is upregulated under hypoxia and modulated by HLF‐2α.…”

Section: Discussionmentioning

confidence: 65%

Positive feedback loop and synergistic effects between hypoxia‐inducible factor‐2α and stearoyl–CoA desaturase‐1 promote tumorigenesis in clear cell renal cell carcinoma

et al. 2013

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Adapting to hypoxic stress is pivotal in tumor progression and determining tumor malignancy. The transcriptional factor hypoxia-inducible factor (HIF) is crucial in modulating tumorous hypoxic responses through altering cell energy metabolism, which includes the modification of glucose and lipid metabolism-associated gene expression. Stearoyl-CoA desaturase-1 (SCD1) is the main isoform of SCDs, the rate-limiting enzymes in the biosynthesis of monounsaturated fatty acids from saturated fatty acids, which is extensively activated in cancer progression. In this study, we found that SCD1 and HIF-2a were overexpressed in human clear cell renal cell carcinoma (ccRCC) tissues and ccRCC cell lines, and were upregulated in the 786-0 ccRCC cell line under hypoxia. Knockdown of SCD1 or HIF-2a impacted the other's expression. Enhancing SCD1 resulted in HIF-2a upregulation, which could be blocked by inhibiting the PI3K ⁄ Akt pathway. Deficiency of SCD1 or HIF-2a in 768-0 cells led to apoptosis, less colony formation ability, and decreased cell migration. More obvious effects were observed in 786-0 cells with double SCD1 and HIF-2a knockdown. These results indicate a PI3K ⁄ Akt-mediated loop between SCD1 and HIF-2a that mutually enhances their protein levels. Both SCD1 and HIF-2a are critical to promoting tumorigenesis by synergistically acting on maintaining cell survival, triggering cell migration, and enhancing the colony formation ability of cancer cells. (Cancer Sci 2013; 104: 416-422) T he von Hippel-Lindau (VHL) protein is a tumor suppression protein whose function is to mediate HIFa degradation and whose gene mutation is commonly found in human ccRCCs.(1) Aberrations in VHL's functions lead to HIFa accumulation irrespective of hydroxylation and upregulation of a series of hypoxia responsive genes in ccRCC.(2) Hypoxiainducible factor is a key transcriptional factor mediating cellular adaptation to hypoxic stress in carcinoma cells. It is an a ⁄ b heterodimeric DNA binding complex that is regulated through stabilization, dissociation, and degradation of subunit HIFa under normoxia.(3) The two best characterized HIFa isoforms are HIF-1a and HIF-2a. Although most of their functions are overlapping, the two isoforms have distinct functions in tumor cells.(4) Moreover, there is an overexpression trend toward HIF-2a rather than HIF-1a in VHL-defective ccRCC cells, (5) which might be due to reciprocal suppression effects between the isoforms. Energy metabolism reprogram is a major consequence after HIFa overexpression. Based on unique activities of these HIFa isoforms, HIF-1a is thought to be primarily involved in glucose metabolism by increasing glucose transporter expression and glycolytic enzymes.(7) Many glucose metabolism-associated genes are regulated by HIF-1a but not HIF-2a.(7) The latter is supposed to participate in angiogenesis modulation, enhancing tumor growth, and triggering cell cycle progression.(6) In another important energy metabolism, lipid metabolism, the two HIFa isoforms showed opposing effects on mo...

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Section: Discussionmentioning

confidence: 65%

Positive feedback loop and synergistic effects between hypoxia‐inducible factor‐2α and stearoyl–CoA desaturase‐1 promote tumorigenesis in clear cell renal cell carcinoma

et al. 2013

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“…To corroborate this point, a recent study using a combined approach of nuclear run on and microarray analysis compared the genetic profile of RAW 264.7 macrophages treated with hypoxia and/or DETA/NONOate [109]. This study identified 162 transcripts that were regulated only when cells were co-treated with hypoxia and NO as well as detecting 14 genes that were under the influence of both hypoxia and NO alone and were differentially regulated by the two treatments in combination.…”

Section: Involvement Of Hif In Inflammatory Diseasesmentioning

confidence: 92%

Interactions between nitric oxide and hypoxia-inducible factor signaling pathways in inflammatory disease

2011

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Induction and activation of nitric oxide (NO) synthases (NOS) and excessive production of NO are common features of almost all diseases associated with infection and acute or chronic inflammation, although the contribution of NO to the pathophysiology of these diseases is highly multifactorial and often still a matter of controversy. Because of its direct impact on tissue oxygenation and cellular oxygen (O 2 ) consumption and redistribution, the ability of NO to regulate various aspects of hypoxia-induced signaling has received widespread attention. Conditions of tissue hypoxia and the activation of hypoxia-inducible factors (HIF) have been implicated in hypoxia or in cancer biology, but are also being increasingly recognized as important features of acute and chronic inflammation. Thus, the activation of HIF transcription factors has been increasingly implicated in inflammatory diseases, and recent studies have indicated its critical importance in regulating phagocyte function, inflammatory mediator production, and regulation of epithelial integrity and repair processes. Finally, HIF also appears to contribute to important features of tissue fibrosis and epithelial-to-mesenchymal transition, processes that are associated with tissue remodeling in various non-malignant chronic inflammatory disorders. In this review, we briefly summarize the current state of knowledge with respect to the general mechanisms involved in HIF regulation and the impact of NO on HIF activation. Secondly, we will summarize the major recent findings demonstrating a role for HIF signaling in infection, inflammation, and tissue repair and remodeling, and will address the involvement of NO. The growing interest in hypoxia-induced signaling and its relation with NO biology is expected to lead to further insights into the complex roles of NO in acute or chronic inflammatory diseases and may point to the importance of HIF signaling as key feature of NO-mediated events during these disorders. Hypoxia, Oxygen Sensing and InflammationDramatic changes in metabolism including increased generation of reactive oxygen and nitrogen species (ROS/RNS), depletion of local nutrients, and an increased demand for oxygen (O 2 ) are characteristic features of the inflammatory response [1]. Increased metabolic activity in inflamed tissue results, in part, from the recruitment of myeloid cells, such as neutrophils and macrophages, to inflammatory lesions and their subsequent involvement in phagocytosis and inflammatory mediator release [2]. These processes, © 2010 Elsevier Inc. All rights reserved. 1 Corresponding author: Department of Pathology, D205 Given Building, 89 Beaumont Avenue, Burlington,.. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the...

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“…Atf3, a stress gene activated by ischemia/hypoxia (41,42), was increased ϳ2.5-fold in cRyr2KO hearts (Fig. 6G).…”

Section: Ryr2 Deletion Reduces Camentioning

confidence: 96%

Cardiomyocyte ATP Production, Metabolic Flexibility, and Survival Require Calcium Flux through Cardiac Ryanodine Receptors in Vivo

Bround

Wambolt

Luciani

et al. 2013

Journal of Biological Chemistry

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Background: Intracellular Ca 2ϩ release has been implicated in ATP production in vitro. Results: In vivo deletion of Ryr2 reduces Ca 2ϩ , ATP, and oxidative metabolism, leading to metabolic reprogramming and cell death. Conclusion: RYR2 maintains cardiomyocyte ATP production and survival in vivo.Significance: This work links heart metabolism to function via Ca 2ϩ release from intracellular stores.

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Hypoxic transcription gene profiles under the modulation of nitric oxide in nuclear run on-microarray and proteomics

Cited by 25 publications

References 51 publications

Positive feedback loop and synergistic effects between hypoxia‐inducible factor‐2α and stearoyl–CoA desaturase‐1 promote tumorigenesis in clear cell renal cell carcinoma

Positive feedback loop and synergistic effects between hypoxia‐inducible factor‐2α and stearoyl–CoA desaturase‐1 promote tumorigenesis in clear cell renal cell carcinoma

Interactions between nitric oxide and hypoxia-inducible factor signaling pathways in inflammatory disease

Cardiomyocyte ATP Production, Metabolic Flexibility, and Survival Require Calcium Flux through Cardiac Ryanodine Receptors in Vivo

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