Hypoxia (Auckland, N.Z.)最新文献

{"title":"The role of HIFs in ischemia-reperfusion injury","authors":"N. Howell, D. Tennant","doi":"10.2147/HP.S49720","DOIUrl":"https://doi.org/10.2147/HP.S49720","url":null,"abstract":"The reduction or cessation of the blood supply to an organ results in tissue ischemia. Ischemia can cause significant tissue damage, and is observed as a result of a thrombosis, as part of a disease process, and during surgery. However, the restoration of the blood supply often causes more damage to the tissue than the ischemic episode itself. Research is therefore focused on identifying the cellular pathways involved in the protection of organs from the damage incurred by this process of ischemia reperfusion (I/R). The hypoxia-inducible factors (HIFs) are a family of heterodimeric transcription factors that are stabilized during ischemia. The genes that are expressed downstream of HIF activity enhance oxygen-independent ATP generation, cell survival, and angiogenesis, amongst other phenotypes. They are, therefore, important factors in the protection of tissues from I/R injury. Interestingly, a number of the mechanisms already known to induce organ protection against I/R injury, including preconditioning, postconditioning, and activation of signaling pathways such as adenosine receptor signaling, converge on the HIF system. This review describes the evidence for HIFs playing a role in I/R protection mediated by these factors, highlights areas that require further study, and discuss whether HIFs themselves are good therapeutic targets for protecting tissues from I/R injury.","PeriodicalId":73270,"journal":{"name":"Hypoxia (Auckland, N.Z.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HP.S49720","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68360836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of hypoxia in pancreatic cancer invasion and metastasis","authors":"A. Yuen, Begoña Díaz","doi":"10.2147/HP.S52636","DOIUrl":"https://doi.org/10.2147/HP.S52636","url":null,"abstract":"Intratumoral hypoxia is a common feature of solid tumors. Recent advances in cancer biology indicate that hypoxia is not only a consequence of unrestrained tumor growth, but also plays an active role in promoting tumor progression, malignancy, and resistance to therapy. Hypoxia signaling is mediated by the hypoxia-inducible factors (HIFs), which are not only stabilized under hypoxia, but also by activated oncogenes or inactivated tumor suppressors under normoxia. Hypoxia is a prominent feature of the tumor microenvironment of pancreatic tumors, also characterized by the presence of a fibrotic reaction that promotes, and is also modulated by, hypoxia. As the mechanisms by which hypoxia signaling impacts invasion and metastasis in pancreatic cancer are being elucidated, hypoxia is emerging as a key determinant of pancreatic cancer malignancy as well as an important target for therapy. Herein we present an overview of recent advances in the understanding of the impact that hypoxia has in pancreatic cancer invasion and metastasis.","PeriodicalId":73270,"journal":{"name":"Hypoxia (Auckland, N.Z.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HP.S52636","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68361027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of PHD2 mutations in the pathogenesis of erythrocytosis","authors":"B. Gardie, M. Percy, D. Hoogewijs, R. Chowdhury, C. Bento, P. Arsenault, S. Richard, H. Almeida, J. Ewing, F. Lambert, M. McMullin, C. Schofield, F. Lee","doi":"10.2147/HP.S54455","DOIUrl":"https://doi.org/10.2147/HP.S54455","url":null,"abstract":"The transcription of the erythropoietin (EPO) gene is tightly regulated by the hypoxia response pathway to maintain oxygen homeostasis. Elevations in serum EPO level may be reflected in an augmentation in the red cell mass, thereby causing erythrocytosis. Studies on erythrocytosis have provided insights into the function of the oxygen-sensing pathway and the critical proteins involved in the regulation of EPO transcription. The α subunits of the hypoxia-inducible transcription factor are hydroxylated by three prolyl hydroxylase domain (PHD) enzymes, which belong to the iron and 2-oxoglutarate-dependent oxygenase superfamily. Sequence analysis of the genes encoding the PHDs in patients with erythrocytosis has revealed heterozygous germline mutations only occurring in Egl nine homolog 1 (EGLN1, also known as PHD2), the gene that encodes PHD2. To date, 24 different EGLN1 mutations comprising missense, frameshift, and nonsense mutations have been described. The phenotypes associated with the patients carrying these mutations are fairly homogeneous and typically limited to erythrocytosis with normal to elevated EPO. However, exceptions exist; for example, there is one case with development of concurrent paraganglioma (PHD2-H374R). Analysis of the erythrocytosis-associated PHD2 missense mutations has shown heterogeneous results. Structural studies reveal that mutations can affect different domains of PHD2. Some are close to the hypoxia-inducible transcription factor α/2-oxoglutarate or the iron binding sites for PHD2. In silico studies demonstrate that the mutations do not always affect fully conserved residues. In vitro and in cellulo studies showed varying effects of the mutations, ranging from mild effects to severe loss of function. The exact mechanism of a potential tumor-suppressor role for PHD2 still needs to be elucidated. A knockin mouse model expressing the first reported PHD2-P317R mutation recapitulates the phenotype observed in humans (erythrocytosis with inappropriately normal serum EPO levels) and demonstrates that haploinsufficiency and partial deregulation of PHD2 is sufficient to cause erythrocytosis.","PeriodicalId":73270,"journal":{"name":"Hypoxia (Auckland, N.Z.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HP.S54455","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68361121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complex role of HIF in cancer: the known, the unknown, and the unexpected","authors":"Patricia D. B. Tiburcio, Hyunsung Choi, L. Huang, Eric L. Huang","doi":"10.2147/HP.S50651","DOIUrl":"https://doi.org/10.2147/HP.S50651","url":null,"abstract":"Tumor hypoxia has long been recognized as a driving force of malignant progression and therapeutic resistance. The discovery of hypoxia-inducible transcription factors (HIFs) has greatly advanced our understanding of how cancer cells cope with hypoxic stress by maintaining bioenergetics through the stimulation of glycolysis. Until recently, however, it remained perplexing why proliferative cancer cells opt for aerobic glycolysis, an energy-inefficient process of glucose metabolism. Furthermore, the role of HIF in cancer has also become complex. In this review, we highlight recent groundbreaking findings in cancer metabolism, put forward plausible explanations to the complex role of HIF, and underscore remaining issues in cancer biology.","PeriodicalId":73270,"journal":{"name":"Hypoxia (Auckland, N.Z.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HP.S50651","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68360881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIF-mediated innate immune responses: cell signaling and therapeutic implications","authors":"Alison J. Harris, A. Thompson, M. Whyte, S. Walmsley","doi":"10.2147/HP.S50269","DOIUrl":"https://doi.org/10.2147/HP.S50269","url":null,"abstract":"Leukocytes recruited to infected, damaged, or inflamed tissues during an immune response must adapt to oxygen levels much lower than those in the circulation. Hypoxia inducible factors (HIFs) are key mediators of cellular responses to hypoxia and, as in other cell types, HIFs are critical for the upregulation of glycolysis, which enables innate immune cells to produce adenosine triphosphate anaerobically. An increasing body of evidence demonstrates that hypoxia also regulates many other innate immunological functions, including cell migration, apoptosis, phagocytosis of pathogens, antigen presentation and production of cytokines, chemokines, and angiogenic and antimicrobial factors. Many of these functions are mediated by HIFs, which are not only stabilized posttranslationally by hypoxia, but also transcriptionally upregulated by inflammatory signals. Here, we review the role of HIFs in the responses of innate immune cells to hypoxia, both in vitro and in vivo, with a particular focus on myeloid cells, on which the majority of studies have so far been carried out.","PeriodicalId":73270,"journal":{"name":"Hypoxia (Auckland, N.Z.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HP.S50269","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68360850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct phosphorylation events involved in HIF-α regulation: the role of GSK-3β","authors":"Daniela Mennerich, E. Dimova, T. Kietzmann","doi":"10.2147/HP.S60703","DOIUrl":"https://doi.org/10.2147/HP.S60703","url":null,"abstract":"Hypoxia-inducible factors (HIFs), consisting of α- and β-subunits, are critical regulators of the transcriptional response to hypoxia under both physiological and pathological conditions. To a large extent, the protein stability and the recruitment of coactivators to the C-terminal transactivation domain of the HIF α-subunits determine overall HIF activity. The regulation of HIF α-subunit protein stability and coactivator recruitment is mainly achieved by oxygen-dependent posttranslational hydroxylation of conserved proline and asparagine residues, respectively. Under hypoxia, the hydroxylation events are inhibited and HIF α-subunits stabilize, translocate to the nucleus, dimerize with the β-subunits, and trigger a transcriptional response. However, under normal oxygen conditions, HIF α-subunits can be activated by various growth and coagulation factors, hormones, cytokines, or stress factors implicating the involvement of different kinase pathways in their regulation, thereby making HIF-α-regulating kinases attractive therapeutic targets. From the kinases known to regulate HIF α-subunits, only a few phosphorylate HIF-α directly. Here, we review the direct phosphorylation of HIF-α with an emphasis on the role of glycogen synthase kinase-3β and the consequences for HIF-1α function.","PeriodicalId":73270,"journal":{"name":"Hypoxia (Auckland, N.Z.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HP.S60703","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68361127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia-inducible factor-mediated induction of WISP-2 contributes to attenuated progression of breast cancer","authors":"Jerry H. Fuady, M. R. Bordoli, Irene Abreu-Rodríguez, G. Kristiansen, D. Hoogewijs, D. Stiehl, R. Wenger","doi":"10.2147/HP.S54404","DOIUrl":"https://doi.org/10.2147/HP.S54404","url":null,"abstract":"Hypoxia and the hypoxia-inducible factor (HIF) signaling pathway trigger the expression of several genes involved in cancer progression and resistance to therapy. Transcriptionally active HIF-1 and HIF-2 regulate overlapping sets of target genes, and only few HIF-2 specific target genes are known so far. Here we investigated oxygen-regulated expression of Wnt-1 induced signaling protein 2 (WISP-2), which has been reported to attenuate the progression of breast cancer. WISP-2 was hypoxically induced in low-invasive luminal-like breast cancer cell lines at both the messenger RNA and protein levels, mainly in a HIF-2α-dependent manner. HIF-2-driven regulation of the WISP2 promoter in breast cancer cells is almost entirely mediated by two phylogenetically and only partially conserved functional hypoxia response elements located in a microsatellite region upstream of the transcriptional start site. High WISP-2 tumor levels were associated with increased HIF-2α, decreased tumor macrophage density, and a better prognosis. Silencing WISP-2 increased anchorage-independent colony formation and recovery from scratches in confluent cell layers of normally low-invasive MCF-7 cancer cells. Interestingly, these changes in cancer cell aggressiveness could be phenocopied by HIF-2α silencing, suggesting that direct HIF-2-mediated transcriptional induction of WISP-2 gene expression might at least partially explain the association of high HIF-2α tumor levels with prolonged overall survival of patients with breast cancer.","PeriodicalId":73270,"journal":{"name":"Hypoxia (Auckland, N.Z.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HP.S54404","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68361048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia and the modulation of the actin cytoskeleton – emerging interrelations","authors":"A. Zieseniss","doi":"10.2147/HP.S53575","DOIUrl":"https://doi.org/10.2147/HP.S53575","url":null,"abstract":"Recent progress in understanding the influence of hypoxia on cell function has revealed new information about the interrelationship between the actin cytoskeleton and hypoxia; nevertheless, details remain cloudy. The dynamic regulation of the actin cytoskeleton during hypoxia is complex, varies in different cells and tissues, and also depends on the mode of hypoxia. Several molecular players and pathways are emerging that contribute to the modulation of the actin cytoskeleton and that affect the large repertoire of actin-binding proteins in hypoxia. This review describes and discusses the accumulated knowledge about actin cytoskeleton dynamics in hypoxia, placing special emphasis on the Rho family of small guanosine triphosphatases (Rho GTPases). Given that RhoA, Rac and Cdc42 are very well characterized, the review is focused on these family members of Rho GTPases. Notably, in several cell types and tissues, hypoxia, presumably via Rho GTPase signaling, induces actin rearrangement and actin stress fiber assembly, which is a prevalent modulation of the actin cytoskeleton in hypoxia.","PeriodicalId":73270,"journal":{"name":"Hypoxia (Auckland, N.Z.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HP.S53575","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68360686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"One more stem cell niche: how the sensitivity of chronic myeloid leukemia cells to imatinib mesylate is modulated within a “hypoxic” environment","authors":"E. Rovida, Ilaria Marzi, M. Cipolleschi, P. Dello Sbarba","doi":"10.2147/HP.S51812","DOIUrl":"https://doi.org/10.2147/HP.S51812","url":null,"abstract":"This is a review (by no means comprehensive) of how the stem cell niche evolved from an abstract concept to a complex system, implemented with a number of experimental data at the cellular and molecular levels, including metabolic cues, on which we focused in particular. The concept was introduced in 1978 to model bone marrow sites suited to host hematopoietic stem cells (HSCs) and favor their self-renewal, while restraining clonal expansion and commitment to differentiation. Studies of the effects of low oxygen tension on HSC maintenance in vitro led us to hypothesize niches were located within bone marrow areas where oxygen tension is lower than elsewhere. We named these areas hypoxic stem cell niches, although a low oxygen tension is to be considered physiological for the environment where HSCs are maintained. HSCs were later shown to have the option of cycling in low oxygen, which steers this cycling to the maintenance of stem cell potential. Cell subsets capable of withstanding incubation in very low oxygen were also detected within leukemia cell populations, including chronic myeloid leukemia (CML). The oncogenetic Bcr/Abl protein is completely suppressed in these subsets, whereas Bcr/Abl messenger ribonucleic acid is not, indicating that CML cells resistant to low oxygen are independent of Bcr/Abl for persistence in culture but remain genetically leukemic. Accordingly, leukemia stem cells of CML selected in low oxygen are refractory to the Bcr/Abl inhibitor imatinib mesylate. Bcr/Abl protein suppression turned out to be actually determined when glucose shortage complicated the effects of low oxygen, indicating that ischemia-like conditions are the driving force of leukemia stem cell refractoriness to imatinib mesylate. These studies pointed to “ischemic” stem cell niches as a novel scenario for the maintenance of minimal residual disease of CML. A possible functional relationship of the “ischemic” with the “hypoxic” stem cell niche is discussed.","PeriodicalId":73270,"journal":{"name":"Hypoxia (Auckland, N.Z.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/HP.S51812","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68361019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia-inducible factor-mediated induction of Wnt-1 induced signaling protein 2 contributes to attenuated progression of breast cancer","authors":"Jerry H. Fuady, M. R. Bordoli, Irene Abreu-Rodríguez, G. Kristiansen, D. Hoogewijs, D. Stiehl, R. Wenger","doi":"10.5167/UZH-107643","DOIUrl":"https://doi.org/10.5167/UZH-107643","url":null,"abstract":"Hypoxia and the hypoxia-inducible factor (HIF) signaling pathway trigger the expression of several genes involved in cancer progression and resistance to therapy. Transcriptionally active HIF-1 and HIF-2 regulate overlapping sets of target genes, and only few HIF-2 specific target genes are known so far. Here we investigated oxygen-regulated expression of Wnt-1 induced signaling protein 2 (WISP-2), which has been reported to attenuate the progression of breast cancer. WISP-2 was hypoxically induced in low-invasive luminal-like breast cancer cell lines at both the messenger RNA and protein levels, mainly in a HIF-2α-dependent manner. HIF-2-driven regulation of the WISP-2 promoter in breast cancer cells is almost entirely mediated by two phylogenetically and only partially conserved functional hypoxia response elements located in a microsatellite region upstream of the transcriptional start site. High WISP-2 tumor levels were associated with increased HIF-2α, decreased tumor macrophage density, and a better prognosis. Silencing WISP-2 increased anchorage-independent colony formation and recovery from scratches in confluent cell layers of normally low-invasive MCF-7 cancer cells. Interestingly, these changes in cancer cell aggressiveness could be phenocopied by HIF-2α silencing, suggesting that direct HIF-2-mediated transcriptional induction of WISP-2 gene expression might at least partially explain the association of high HIF-2α tumor levels with prolonged overall survival of patients with breast cancer.","PeriodicalId":73270,"journal":{"name":"Hypoxia (Auckland, N.Z.)","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70633873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}