The Experts below are selected from a list of 5625 Experts worldwide ranked by ideXlab platform
Marianne Koritzinsky - One of the best experts on this subject based on the ideXlab platform.
-
Hypoxia Signalling through mtor and the unfolded protein response in cancer
Nature Reviews Cancer, 2008Co-Authors: Bradly G. Wouters, Marianne KoritzinskyAbstract:Responses to Hypoxia are orchestrated not only through activation of the Hypoxia–inducible factor family of transcription factors (HIFs), but also through HIF–independent Signalling pathways. How are these pathways integrated?
-
Hypoxia Signalling through mTOR and the unfolded protein response in cancer
Nature Reviews Cancer, 2008Co-Authors: Bradly G. Wouters, Marianne KoritzinskyAbstract:Hypoxia occurs in the majority of tumours, promoting angiogenesis, metastasis and resistance to therapy. Responses to Hypoxia are orchestrated in part through activation of the Hypoxia-inducible factor family of transcription factors (HIFs). Recently, two additional O(2)-sensitive Signalling pathways have also been implicated: Signalling through the mammalian target of rapamycin (mTOR) kinase and Signalling through activation of the unfolded protein response (UPR). Although they are activated independently, growing evidence suggests that HIF-, mTOR- and UPR-dependent responses to Hypoxia act in an integrated way, influencing each other and common downstream pathways that affect gene expression, metabolism, cell survival, tumorigenesis and tumour growth.
Andrew J. Murray - One of the best experts on this subject based on the ideXlab platform.
-
energy metabolism and the high altitude environment
Experimental Physiology, 2016Co-Authors: Andrew J. MurrayAbstract:New Findings What is the topic of this review? This report describes changes in cardiac and skeletal muscle energy metabolism that occur with exposure to high altitude and considers possible underlying mechanisms. What advances does it highlight? In the human heart, sustained Hypoxia at high altitude or shorter-term normobaric Hypoxia result in a loss of cardiac energetic reserve. In the hypoxic rat heart, fatty acid oxidation and respiratory capacity fall. In skeletal muscle, prolonged exposure to extreme high altitude results in the loss of mitochondrial density, but even at more moderate high altitude the respiratory capacity may be suppressed. Evidence from cells, genetically modified mice and high-altitude-adapted Tibetans suggests a possible mechanistic role for the Hypoxia-inducible factor pathway. At high altitude the barometric pressure falls, challenging oxygen delivery to the tissues. Thus, whilst Hypoxia is not the only physiological stress encountered at high altitude, low arterial PO2 is a sustained feature, even after allowing adequate time for acclimatization. Cardiac and skeletal muscle energy metabolism is altered in subjects at, or returning from, high altitude. In the heart, energetic reserve falls, as indicated by lower phosphocreatine-to-ATP ratios. The underlying mechanism is unknown, but in the hypoxic rat heart fatty acid oxidation and respiratory capacity are decreased, whilst pyruvate oxidation is also lower after sustained hypoxic exposure. In skeletal muscle, there is not a consensus. With prolonged exposure to extreme high altitude (>5500 m) a loss of muscle mitochondrial density is seen, but this was not observed in a simulated ascent of Everest in hypobaric chambers. At more moderate high altitude, decreased respiratory capacity may occur without changes in mitochondrial volume density, and fat oxidation may be downregulated, although this is not seen in all studies. The underlying mechanisms, including the possible role of Hypoxia-Signalling pathways, remain to be resolved, particularly in light of confounding factors in the high-altitude environment. In high-altitude-adapted Tibetan natives, however, there is evidence of natural selection centred around the Hypoxia-inducible factor pathway, and metabolic features in this population (e.g. low cardiac phosphocreatine-to-ATP ratios, increased cardiac glucose uptake and lower muscle mitochondrial densities) share similarities with those in acclimatized lowlanders, supporting a possible role for the Hypoxia-inducible factor pathway in the metabolic response of cardiac and skeletal muscle energy metabolism to high altitude.
-
energy metabolism and the high altitude environment
Experimental Physiology, 2016Co-Authors: Andrew J. MurrayAbstract:At high altitude the barometric pressure falls, challenging oxygen delivery to the tissues. Thus, whilst Hypoxia is not the only physiological stress encountered at high altitude, low arterial P(O2) is a sustained feature, even after allowing adequate time for acclimatization. Cardiac and skeletal muscle energy metabolism is altered in subjects at, or returning from, high altitude. In the heart, energetic reserve falls, as indicated by lower phosphocreatine-to-ATP ratios. The underlying mechanism is unknown, but in the hypoxic rat heart fatty acid oxidation and respiratory capacity are decreased, whilst pyruvate oxidation is also lower after sustained hypoxic exposure. In skeletal muscle, there is not a consensus. With prolonged exposure to extreme high altitude (>5500 m) a loss of muscle mitochondrial density is seen, but this was not observed in a simulated ascent of Everest in hypobaric chambers. At more moderate high altitude, decreased respiratory capacity may occur without changes in mitochondrial volume density, and fat oxidation may be downregulated, although this is not seen in all studies. The underlying mechanisms, including the possible role of Hypoxia-Signalling pathways, remain to be resolved, particularly in light of confounding factors in the high-altitude environment. In high-altitude-adapted Tibetan natives, however, there is evidence of natural selection centred around the Hypoxia-inducible factor pathway, and metabolic features in this population (e.g. low cardiac phosphocreatine-to-ATP ratios, increased cardiac glucose uptake and lower muscle mitochondrial densities) share similarities with those in acclimatized lowlanders, supporting a possible role for the Hypoxia-inducible factor pathway in the metabolic response of cardiac and skeletal muscle energy metabolism to high altitude.
Peter J Ratcliffe - One of the best experts on this subject based on the ideXlab platform.
-
mechanisms of Hypoxia Signalling new implications for nephrology
Nature Reviews Nephrology, 2019Co-Authors: Johannes Schodel, Peter J RatcliffeAbstract:Studies of the regulation of erythropoietin (EPO) production by the liver and kidneys, one of the classical physiological responses to Hypoxia, led to the discovery of human oxygen-sensing mechanisms, which are now being targeted therapeutically. The oxygen-sensitive signal is generated by 2-oxoglutarate-dependent dioxygenases that deploy molecular oxygen as a co-substrate to catalyse the post-translational hydroxylation of specific prolyl and asparaginyl residues in Hypoxia-inducible factor (HIF), a key transcription factor that regulates transcriptional responses to Hypoxia. Hydroxylation of HIF at different sites promotes both its degradation and inactivation. Under hypoxic conditions, these processes are suppressed, enabling HIF to escape destruction and form active transcriptional complexes at thousands of loci across the human genome. Accordingly, HIF prolyl hydroxylase inhibitors stabilize HIF and stimulate expression of HIF target genes, including the EPO gene. These molecules activate endogenous EPO gene expression in diseased kidneys and are being developed, or are already in clinical use, for the treatment of renal anaemia. In this Review, we summarize information on the molecular circuitry of Hypoxia Signalling pathways underlying these new treatments and highlight some of the outstanding questions relevant to their clinical use.
-
abstract p2 05 01 the non coding transcriptome of hypoxic breast cancer novel insights of clinical relevant long non coding rna in Hypoxia Signalling
Cancer Research, 2015Co-Authors: Peter J Ratcliffe, Johannes Schodel, Hani Choudhry, Ashwag Albukhari, Syed Haider, Francesca M Buffa, David R Mole, Ioannis Ragousis, Adrian L HarrisAbstract:Hypoxia is associated with aggressive and poor prognosis of breast cancer. Generally, pan-genome analyses of Hypoxia have focussed on protein-coding genes, however, the role of non-coding RNAs, in particular long non-coding RNAs (lncRNA) in Hypoxia is not well characterised. We undertook an integrated genomic analysis of the hypoxic transcriptome in MCF7 breast cancer cells, employing total RNA-seq together with ChIP-seq for the Hypoxia-inducible transcription factor (HIF) and for epigenetic marks of transcriptional activation (RNApol2 and histone H3K4me3). Analyses revealed that all classes of RNA are significantly regulated by Hypoxia including piwiRNA, miRNA, tRNA, and sn/snoRNA. Significant numbers of lncRNAs were upregulated in Hypoxia and were associated with increased RNApol2 and H3K4me3 markers and with HIF binding, indicating direct transcriptional activation of lncRNAs by HIF. The most hypoxiclly upregulated lncRNA was NEAT1, which is a direct transcriptional target of HIF-2a but not HIF-1a. The role of NEAT1 in cancer has not been previously studied. We demonstrated that hypoxic NEAT1 induction is common in breast cancer cell lines and xenografts models treated with bevacizumab. NEAT1 directly induces the formation of nuclear paraspeckle bodies in Hypoxia. Moreover, it contributes to tumourigenicity by increasing cell proliferation, colony formation, and reducing apoptosis. In addition, we report that NEAT1 is required to retain Hypoxia induced hyper edited Junctional Adhesion Molecule A (JAM-A) mRNA in the nucleus, thus preventing export into the cytoplasm for translation. Finally, in a large cohort of 2000 breast cancers, high levels of NEAT1 were associated with poor clinical outcomes and clinicopathological features. Our results extend knowledge of the hypoxic transcriptional response into the spectrum of non-coding transcripts. These findings provide novel mechanisms of transcriptional regulation in Hypoxia and open new avenues to find novel pathways and targets to develop therapies for breast cancer. Citation Format: Hani Choudhry, Johannes Schodel, Ashwag Albukhari, Syed Haider, Francesca Buffa, Peter J Ratcliffe, David R Mole, Ioannis Ragousis, Adrian L Harris. The non-coding transcriptome of hypoxic breast cancer: Novel insights of clinical relevant long non-coding RNA in Hypoxia Signalling [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-05-01.
-
oxygen sensing and Hypoxia Signalling pathways in animals the implications of physiology for cancer
The Journal of Physiology, 2013Co-Authors: Peter J RatcliffeAbstract:Studies of regulation of the haematopoietic growth factor erythropoietin led to the unexpected discovery of a widespread system of direct oxygen sensing that regulates gene expression in animals. The oxygen-sensitive signal is generated by a series of non-haem Fe(II)- and 2-oxoglutarate-dependent dioxygenases that catalyse the post-translational hydroxylation of specific residues in the transcription factor Hypoxia-inducible factor (HIF). These hydroxylations promote both oxygen-dependent degradation and oxygen-dependent inactivation of HIF, but are suppressed in Hypoxia, leading to the accumulation of HIF and assembly of an active transcriptional complex in hypoxic cells. Hypoxia-inducible factor activates an extensive transcriptional cascade that interfaces with other cell Signalling pathways, microRNA networks and RNA-protein translational control systems. The relationship of these cellular Signalling pathways to the integrated physiology of oxygen homeostasis and the implication of dysregulating these massive physiological pathways in diseases such as cancer are discussed.
Bradly G. Wouters - One of the best experts on this subject based on the ideXlab platform.
-
Hypoxia Signalling through mtor and the unfolded protein response in cancer
Nature Reviews Cancer, 2008Co-Authors: Bradly G. Wouters, Marianne KoritzinskyAbstract:Responses to Hypoxia are orchestrated not only through activation of the Hypoxia–inducible factor family of transcription factors (HIFs), but also through HIF–independent Signalling pathways. How are these pathways integrated?
-
Hypoxia Signalling through mTOR and the unfolded protein response in cancer
Nature Reviews Cancer, 2008Co-Authors: Bradly G. Wouters, Marianne KoritzinskyAbstract:Hypoxia occurs in the majority of tumours, promoting angiogenesis, metastasis and resistance to therapy. Responses to Hypoxia are orchestrated in part through activation of the Hypoxia-inducible factor family of transcription factors (HIFs). Recently, two additional O(2)-sensitive Signalling pathways have also been implicated: Signalling through the mammalian target of rapamycin (mTOR) kinase and Signalling through activation of the unfolded protein response (UPR). Although they are activated independently, growing evidence suggests that HIF-, mTOR- and UPR-dependent responses to Hypoxia act in an integrated way, influencing each other and common downstream pathways that affect gene expression, metabolism, cell survival, tumorigenesis and tumour growth.
Maurice A M Van Steensel - One of the best experts on this subject based on the ideXlab platform.
-
immunohistochemical analysis of the mechanistic target of rapamycin and Hypoxia Signalling pathways in basal cell carcinoma and trichoepithelioma
PLOS ONE, 2014Co-Authors: Tjinta Brinkhuizen, Chantal A H Weijzen, Jonathan Eben, Monique R T M Thissen, Arie Nne M Van Marion, Bjo Rn G Lohman, Veronique Winnepenninckx, Patty J Nelemans, Maurice A M Van SteenselAbstract:Background Basal cell carcinoma (BCC) is the most common cancer in Caucasians. Trichoepithelioma (TE) is a benign neoplasm that strongly resembles BCC. Both are hair follicle (HF) tumours. HFs are hypoxic microenvironments, therefore we hypothesized that Hypoxia-induced Signalling pathways could be involved in BCC and TE as they are in other human malignancies. Hypoxia-inducible factor 1 (HIF1) and mechanistic/mammalian target of rapamycin (mTOR) are key players in these pathways.