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Melanson, Gaelan, Sara Timpano, and James Uniacke. "The eIF4E2-Directed Hypoxic Cap-Dependent Translation Machinery Reveals Novel Therapeutic Potential for Cancer Treatment." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/6098107.
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Hypoxia is an aspect of the tumor microenvironment that is linked to radiation and chemotherapy resistance, metastasis, and poor prognosis. The ability of hypoxic tumor cells to achieve these cancer hallmarks is, in part, due to changes in their gene expression profiles. Cancer cells have a high demand for protein synthesis, and translational control is subsequently deregulated. Various mechanisms of translation initiation are active to improve the translation efficiency of select transcripts to drive cancer progression. This review will focus on a noncanonical cap-dependent translation initiation mechanism that utilizes the eIF4E homolog eIF4E2, a hypoxia-activated cap-binding protein that is implicated in hypoxic cancer cell migration, invasion, and tumor growth in mouse xenografts. A historical perspective about eIF4E2 and its various aliases will be provided followed by an evaluation of potential therapeutic strategies. The recent successes of disabling canonical translation and eIF4E with drugs should highlight the novel therapeutic potential of targeting the homologous eIF4E2 in the treatment of hypoxic solid tumors.
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Blais, Jaime D., Vasilisa Filipenko, Meixia Bi, Heather P. Harding, David Ron, Costas Koumenis, Bradly G. Wouters, and John C. Bell. "Activating Transcription Factor 4 Is Translationally Regulated by Hypoxic Stress." Molecular and Cellular Biology 24, no. 17 (September 1, 2004): 7469–82. http://dx.doi.org/10.1128/mcb.24.17.7469-7482.2004.
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ABSTRACT Hypoxic stress results in a rapid and sustained inhibition of protein synthesis that is at least partially mediated by eukaryotic initiation factor 2α (eIF2α) phosphorylation by the endoplasmic reticulum (ER) kinase PERK. Here we show through microarray analysis of polysome-bound RNA in aerobic and hypoxic HeLa cells that a subset of transcripts are preferentially translated during hypoxia, including activating transcription factor 4 (ATF4), an important mediator of the unfolded protein response. Changes in mRNA translation during the unfolded protein response are mediated by PERK phosphorylation of the translation initiation factor eIF2α at Ser-51. Similarly, PERK is activated and is responsible for translational regulation under hypoxic conditions, while inducing the translation of ATF4. The overexpression of a C-terminal fragment of GADD34 that constitutively dephosphorylates eIF2α was able to attenuate the phosphorylation of eIF2α and severely inhibit the induction of ATF4 in response to hypoxic stress. These studies demonstrate the essential role of ATF4 in the response to hypoxic stress, define the pathway for its induction, and reveal that GADD34, a target of ATF4 activation, negatively regulates the eIF2α-mediated inhibition of translation. Taken with the concomitant induction of additional ER-resident proteins identified by our microarray analysis, this study suggests an important integrated response between ER signaling and the cellular adaptation to hypoxic stress.
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Mao, Xianrong R., and C. Michael Crowder. "Protein Misfolding Induces Hypoxic Preconditioning via a Subset of the Unfolded Protein Response Machinery." Molecular and Cellular Biology 30, no. 21 (August 23, 2010): 5033–42. http://dx.doi.org/10.1128/mcb.00922-10.
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ABSTRACT Prolonged cellular hypoxia results in energy failure and ultimately cell death. However, less-severe hypoxia can induce a cytoprotective response termed hypoxic preconditioning (HP). The unfolded protein response pathway (UPR) has been known for some time to respond to hypoxia and regulate hypoxic sensitivity; however, the role of the UPR, if any, in HP essentially has been unexplored. We have shown previously that a sublethal hypoxic exposure of the nematode Caenorhabditis elegans induces a protein chaperone component of the UPR (L. L. Anderson, X. Mao, B. A. Scott, and C. M. Crowder, Science 323:630-633, 2009). Here, we show that HP induces the UPR and that the pharmacological induction of misfolded proteins is itself sufficient to stimulate a delayed protective response to hypoxic injury that requires the UPR pathway proteins IRE-1, XBP-1, and ATF-6. HP also required IRE-1 but not XBP-1 or ATF-6; instead, GCN-2, which is known to suppress translation and induce an adaptive transcriptional response under conditions of UPR activation or amino acid deprivation, was required for HP. The phosphorylation of the translation factor eIF2α, an established mechanism of GCN-2-mediated translational suppression, was not necessary for HP. These data suggest a model where hypoxia-induced misfolded proteins trigger the activation of IRE-1, which along with GCN-2 controls an adaptive response that is essential to HP.
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Cho, Sung-Yup, Seungun Lee, Jeonghun Yeom, Hyo-Jun Kim, Jin-Haeng Lee, Ji-Woong Shin, Mee-ae Kwon, et al. "Transglutaminase 2 mediates hypoxia-induced selective mRNA translation via polyamination of 4EBPs." Life Science Alliance 3, no. 3 (February 19, 2020): e201900565. http://dx.doi.org/10.26508/lsa.201900565.
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Hypoxia selectively enhances mRNA translation despite suppressed mammalian target of rapamycin complex 1 activity, contributing to gene expression reprogramming that promotes metastasis and survival of cancer cells. Little is known about how this paradoxical control of translation occurs. Here, we report a new pathway that links hypoxia to selective mRNA translation. Transglutaminase 2 (TG2) is a hypoxia-inducible factor 1–inducible enzyme that alters the activity of substrate proteins by polyamination or crosslinking. Under hypoxic conditions, TG2 polyaminated eukaryotic translation initiation factor 4E (eIF4E)-bound eukaryotic translation initiation factor 4E-binding proteins (4EBPs) at conserved glutamine residues. 4EBP1 polyamination enhances binding affinity for Raptor, thereby increasing phosphorylation of 4EBP1 and cap-dependent translation. Proteomic analyses of newly synthesized proteins in hypoxic cells revealed that TG2 activity preferentially enhanced the translation of a subset of mRNA containing G/C-rich 5′UTRs but not upstream ORF or terminal oligopyrimidine motifs. These results indicate that TG2 is a critical regulator in hypoxia-induced selective mRNA translation and provide a promising molecular target for the treatment of cancers.
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Connor, John H., Christine Naczki, Costas Koumenis, and Douglas S. Lyles. "Replication and Cytopathic Effect of Oncolytic Vesicular Stomatitis Virus in Hypoxic Tumor Cells In Vitro and In Vivo." Journal of Virology 78, no. 17 (September 1, 2004): 8960–70. http://dx.doi.org/10.1128/jvi.78.17.8960-8970.2004.
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ABSTRACT Tumor hypoxia presents an obstacle to the effectiveness of most antitumor therapies, including treatment with oncolytic viruses. In particular, an oncolytic virus must be resistant to the inhibition of DNA, RNA, and protein synthesis that occurs during hypoxic stress. Here we show that vesicular stomatitis virus (VSV), an oncolytic RNA virus, is capable of replication under hypoxic conditions. In cells undergoing hypoxic stress, VSV infection produced larger amounts of mRNA than under normoxic conditions. However, translation of these mRNAs was reduced at earlier times postinfection in hypoxia-adapted cells than in normoxic cells. At later times postinfection, VSV overcame a hypoxia-associated increase in α subunit of eukaryotic initiation factor 2 (eIF-2α) phosphorylation and initial suppression of viral protein synthesis in hypoxic cells to produce large amounts of viral protein. VSV infection caused the dephosphorylation of the translation initiation factor eIF-4E and inhibited host translation similarly under both normoxic and hypoxic conditions. VSV produced progeny virus to similar levels in hypoxic and normoxic cells and showed the ability to expand from an initial infection of 1% of hypoxic cells to spread through an entire population. In all cases, virus infection induced classical cytopathic effects and apoptotic cell death. When VSV was used to treat tumors established in nude mice, we found VSV replication in hypoxic areas of these tumors. This occurred whether the virus was administered intratumorally or intravenously. These results show for the first time that VSV has an inherent capacity for infecting and killing hypoxic cancer cells. This ability could represent a critical advantage over existing therapies in treating established tumors.
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Hettiarachchi, Gaya K., Upendra K. Katneni, Ryan C. Hunt, Jacob M. Kames, John C. Athey, Haim Bar, Zuben E. Sauna, Joseph R. McGill, Juan C. Ibla, and Chava Kimchi-Sarfaty. "Translational and transcriptional responses in human primary hepatocytes under hypoxia." American Journal of Physiology-Gastrointestinal and Liver Physiology 316, no. 6 (June 1, 2019): G720—G734. http://dx.doi.org/10.1152/ajpgi.00331.2018.
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The liver is the primary source of a large number of plasma proteins and plays a critical role in multiple biological processes. Inadequate oxygen supply characterizing various clinical settings such as liver transplantation exposes the liver to hypoxic conditions. Studies assessing hypoxia-induced global translational changes in liver are lacking. Here, we employed a recently developed ribosome-profiling technique to assess global translational responses of human primary hepatocytes exposed to acute hypoxic stress (1% O2) for the short term. In parallel, transcriptome profiling was performed to assess mRNA expression changes. We found that translational responses appeared earlier and were predominant over transcriptional responses. A significant decrease in translational efficiency of several ribosome genes indicated translational inhibition of new ribosome protein synthesis in hypoxia. Pathway enrichment analysis highlighted altered translational regulation of MAPK signaling, drug metabolism, oxidative phosphorylation, and nonalcoholic fatty liver disease pathways. Gene Ontology enrichment analysis revealed terms related to translation, metabolism, angiogenesis, apoptosis, and response to stress. Transcriptional induction of genes encoding heat shock proteins was observed within 30 min of hypoxia. Induction of genes encoding stress response mediators, metabolism regulators, and proangiogenic proteins was observed at 240 min. Despite the liver being the primary source of coagulation proteins and the implicated role of hypoxia in thrombosis, limited differences were observed in genes encoding coagulation-associated proteins. Overall, our study demonstrates the predominance of translational regulation over transcription and highlights differentially regulated pathways or biological processes in short-term hypoxic stress responses of human primary hepatocytes.NEW & NOTEWORTHY The novelty of this study lies in applying parallel ribosome- and transcriptome-profiling analyses to human primary hepatocytes in hypoxia. To our knowledge, this is the first study to assess global translational responses using ribosome profiling in hypoxic hepatocytes. Our results demonstrate the predominance of translational responses over transcriptional responses in early hepatic hypoxic stress responses. Furthermore, our study reveals multiple pathways and specific genes showing altered regulation in hypoxic hepatocytes.
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Ron, David, and Alan G. Hinnebusch. "Targeting Translation in Hypoxic Tumors." ACS Chemical Biology 1, no. 3 (April 2006): 145–48. http://dx.doi.org/10.1021/cb600125y.
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Lang, Kenneth J. D., Andreas Kappel, and Gregory J. Goodall. "Hypoxia-inducible Factor-1α mRNA Contains an Internal Ribosome Entry Site That Allows Efficient Translation during Normoxia and Hypoxia." Molecular Biology of the Cell 13, no. 5 (May 2002): 1792–801. http://dx.doi.org/10.1091/mbc.02-02-0017.
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HIF-1α is the regulated subunit of the HIF-1 transcription factor, which induces transcription of a number of genes involved in the cellular response to hypoxia. The HIF-1α protein is rapidly degraded in cells supplied with adequate oxygen but is stabilized in hypoxic cells. Using polysome profile analysis, we found that translation of HIF-1α mRNA in NIH3T3 cells is spared the general reduction in translation rate that occurs during hypoxia. To assess whether the 5′UTR of the HIF-1α mRNA contains an internal ribosome entry site (IRES), we constructed a dicistronic reporter with the HIF-1α 5′UTR inserted between two reporter coding regions. We found that the HIF-1α 5′UTR promoted translation of the downstream reporter, indicating the presence of an IRES. The IRES had activity comparable to that of the well-characterized c-myc IRES. IRES activity was not affected by hypoxic conditions that caused a reduction in cap-dependent translation, and IRES activity was less affected by serum-starvation than was cap-dependent translation. These data indicate that the presence of an IRES in the HIF-1α 5′UTR allows translation to be maintained under conditions that are inhibitory to cap-dependent translation.
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Vumbaca, Frank, Kathryn N. Phoenix, Daniel Rodriguez-Pinto, David K. Han, and Kevin P. Claffey. "Double-Stranded RNA-Binding Protein Regulates Vascular Endothelial Growth Factor mRNA Stability, Translation, and Breast Cancer Angiogenesis." Molecular and Cellular Biology 28, no. 2 (November 26, 2007): 772–83. http://dx.doi.org/10.1128/mcb.02078-06.
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ABSTRACT Vascular endothelial growth factor (VEGF) is a key angiogenic factor expressed under restricted nutrient and oxygen conditions in most solid tumors. The expression of VEGF under hypoxic conditions requires transcription through activated hypoxia-inducible factor 1 (HIF-1), increased mRNA stability, and facilitated translation. This study identified double-stranded RNA-binding protein 76/NF90 (DRBP76/NF90), a specific isoform of the DRBP family, as a VEGF mRNA-binding protein which plays a key role in VEGF mRNA stability and protein synthesis under hypoxia. The DRBP76/NF90 protein binds to a human VEGF 3′ untranslated mRNA stability element. RNA interference targeting the DRBP76/NF90 isoform limited hypoxia-inducible VEGF mRNA and protein expression with no change in HIF-1-dependent transcriptional activity. Stable repression of DRBP76/NF90 in MDA-MB-435 breast cancer cells demonstrated reduced polysome-associated VEGF mRNA levels under hypoxic conditions and reduced mRNA stability. Transient overexpression of the DRBP76/NF90 protein increased both VEGF mRNA and protein levels synthesized under normoxic and hypoxic conditions. Cells with stable repression of the DRBP76/NF90 isoform showed reduced tumorigenic and angiogenic potential in an orthotopic breast tumor model. These data demonstrate that the DRBP76/NF90 isoform facilitates VEGF expression by promoting VEGF mRNA loading onto polysomes and translation under hypoxic conditions, thus promoting breast cancer growth and angiogenesis in vivo.
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Ivanova, Iglika G., Catherine V. Park, and Niall S. Kenneth. "Translating the Hypoxic Response—the Role of HIF Protein Translation in the Cellular Response to Low Oxygen." Cells 8, no. 2 (February 1, 2019): 114. http://dx.doi.org/10.3390/cells8020114.
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Hypoxia-Inducible Factors (HIFs) play essential roles in the physiological response to low oxygen in all multicellular organisms, while their deregulation is associated with human diseases. HIF levels and activity are primarily controlled by the availability of the oxygen-sensitive HIFα subunits, which is mediated by rapid alterations to the rates of HIFα protein production and degradation. While the pathways that control HIFα degradation are understood in great detail, much less is known about the targeted control of HIFα protein synthesis and what role this has in controlling HIF activity during the hypoxic response. This review will focus on the signalling pathways and RNA binding proteins that modulate HIFα mRNA half-life and/or translation rate, and their contribution to hypoxia-associated diseases.
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Kenneth, Niall Steven, and Sonia Rocha. "Regulation of gene expression by hypoxia." Biochemical Journal 414, no. 1 (July 29, 2008): 19–29. http://dx.doi.org/10.1042/bj20081055.
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Hypoxia induces profound changes in the cellular gene expression profile. The discovery of a major transcription factor family activated by hypoxia, HIF (hypoxia-inducible factor), and the factors that contribute to HIF regulation have greatly enhanced our knowledge of the molecular aspects of the hypoxic response. However, in addition to HIF, other transcription factors and cellular pathways are activated by exposure to reduced oxygen. In the present review, we summarize the current knowledge of how additional hypoxia-responsive transcription factors integrate with HIF and how other cellular pathways such as chromatin remodelling, translation regulation and microRNA induction, contribute to the co-ordinated cellular response observed following hypoxic stress.
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Wilkinson, Katherine A., Kimberly Huey, Bruce Dinger, Liang He, Salvatore Fidone, and Frank L. Powell. "Chronic hypoxia increases the gain of the hypoxic ventilatory response by a mechanism in the central nervous system." Journal of Applied Physiology 109, no. 2 (August 2010): 424–30. http://dx.doi.org/10.1152/japplphysiol.01311.2009.
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We studied the effects of the ventilatory stimulant doxapram to test the hypothesis that chronic hypoxia increases the translation of carotid body afferent input into ventilatory motor efferent output by the central nervous system. Chronic hypoxia (inspired Po2 = 70 Torr, 2 days) significantly increased the ventilatory response to an intravenous infusion of a high dose of doxapram in conscious, unrestrained rats breathing normoxic or hypoxic gas. The in vitro carotid body response to hypoxia increased with chronic hypoxia, but the response was not increased with a high dose of doxapram. Similarly, the phrenic nerve response to doxapram in anesthetized rats with carotid bodies denervated did not change with 7 days of chronic hypoxia. The results support the hypothesis that chronic hypoxia causes plasticity in the central component of the carotid chemoreceptor ventilatory reflex, which increases the hypoxic ventilatory response. We conclude that doxapram provides a promising tool to study the time course of changes in the central gain of the hypoxic ventilatory response during chronic hypoxia in awake animals and humans.
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Koumenis, Constantinos, Christine Naczki, Marianne Koritzinsky, Sally Rastani, Alan Diehl, Nahum Sonenberg, Antonis Koromilas, and Bradly G. Wouters. "Regulation of Protein Synthesis by Hypoxia via Activation of the Endoplasmic Reticulum Kinase PERK and Phosphorylation of the Translation Initiation Factor eIF2α." Molecular and Cellular Biology 22, no. 21 (November 1, 2002): 7405–16. http://dx.doi.org/10.1128/mcb.22.21.7405-7416.2002.
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ABSTRACT Hypoxia profoundly influences tumor development and response to therapy. While progress has been made in identifying individual gene products whose synthesis is altered under hypoxia, little is known about the mechanism by which hypoxia induces a global downregulation of protein synthesis. A critical step in the regulation of protein synthesis in response to stress is the phosphorylation of translation initiation factor eIF2α on Ser51, which leads to inhibition of new protein synthesis. Here we report that exposure of human diploid fibroblasts and transformed cells to hypoxia led to phosphorylation of eIF2α, a modification that was readily reversed upon reoxygenation. Expression of a transdominant, nonphosphorylatable mutant allele of eIF2α attenuated the repression of protein synthesis under hypoxia. The endoplasmic reticulum (ER)-resident eIF2α kinase PERK was hyperphosphorylated upon hypoxic stress, and overexpression of wild-type PERK increased the levels of hypoxia-induced phosphorylation of eIF2α. Cells stably expressing a dominant-negative PERK allele and mouse embryonic fibroblasts with a homozygous deletion of PERK exhibited attenuated phosphorylation of eIF2α and reduced inhibition of protein synthesis in response to hypoxia. PERK−/− mouse embryo fibroblasts failed to phosphorylate eIF2α and exhibited lower survival after prolonged exposure to hypoxia than did wild-type fibroblasts. These results indicate that adaptation of cells to hypoxic stress requires activation of PERK and phosphorylation of eIF2α and suggest that the mechanism of hypoxia-induced translational attenuation may be linked to ER stress and the unfolded-protein response.
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Tatsumi, Koichiro, Cheryl K. Pickett, Christopher R. Jacoby, John V. Weil, and Lorna G. Moore. "Role of endogenous female hormones in hypoxic chemosensitivity." Journal of Applied Physiology 83, no. 5 (November 1, 1997): 1706–10. http://dx.doi.org/10.1152/jappl.1997.83.5.1706.
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Tatsumi, Koichiro, Cheryl K. Pickett, Christopher R. Jacoby, John V. Weil, and Lorna G. Moore. Role of endogenous female hormones in hypoxic chemosensitivity. J. Appl. Physiol. 83(5): 1706–1710, 1997.—Effective alveolar ventilation and hypoxic ventilatory response (HVR) are higher in females than in males and after endogenous or exogenous elevation of progesterone and estrogen. The contribution of normal physiological levels of ovarian hormones to resting ventilation and ventilatory control and whether their site(s) of action is central and/or peripheral are unclear. Accordingly, we examined resting ventilation, HVR, and hypercapnic ventilatory responses (HCVR) before and 3 wk after ovariectomy in five female cats. We also compared carotid sinus nerve (CSN) and central nervous system translation responses to hypoxia in 6 ovariectomized and 24 intact female animals. Ovariectomy decreased serum progesterone but did not change resting ventilation, end-tidal[Formula: see text], or HCVR (all P = NS). Ovariectomy reduced the HVR shape parameter A in the awake (38.9 ± 5.5 and 21.2 ± 3.0 before and after ovariectomy, respectively, P < 0.05) and anesthetized conditions. The CSN response to hypoxia was lower in ovariectomized than in intact animals (shape parameter A = 22.6 ± 2.5 and 54.3 ± 3.5 in ovariectomized and intact animals, respectively, P < 0.05), but central nervous system translation of CSN activity into ventilation was similar in ovariectomized and intact animals. We concluded that ovariectomy decreased ventilatory and CSN responsiveness to hypoxia, suggesting that the presence of physiological levels of ovarian hormones influences hypoxic chemosensitivity by acting primarily at peripheral sites.
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Nakayama, Koh, and Naoyuki Kataoka. "Regulation of Gene Expression under Hypoxic Conditions." International Journal of Molecular Sciences 20, no. 13 (July 3, 2019): 3278. http://dx.doi.org/10.3390/ijms20133278.
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Eukaryotes are often subjected to different kinds of stress. In order to adjust to such circumstances, eukaryotes activate stress–response pathways and regulate gene expression. Eukaryotic gene expression consists of many different steps, including transcription, RNA processing, RNA transport, and translation. In this review article, we focus on both transcriptional and post-transcriptional regulations of gene expression under hypoxic conditions. In the first part of the review, transcriptional regulations mediated by various transcription factors including Hypoxia-Inducible Factors (HIFs) are described. In the second part, we present RNA splicing regulations under hypoxic conditions, which are mediated by splicing factors and their kinases. This work summarizes and discusses the emerging studies of those two gene expression machineries under hypoxic conditions.
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Vizek, M., C. K. Pickett, and J. V. Weil. "Interindividual variation in hypoxic ventilatory response: potential role of carotid body." Journal of Applied Physiology 63, no. 5 (November 1, 1987): 1884–89. http://dx.doi.org/10.1152/jappl.1987.63.5.1884.
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There is considerable interindividual variation in ventilatory response to hypoxia in humans but the mechanism remains unknown. To examine the potential contribution of variable peripheral chemorecptor function to variation in hypoxic ventilatory response (HVR), we compared the peripheral chemoreceptor and ventilatory response to hypoxia in 51 anesthetized cats. We found large interindividual differences in HVR spanning a sevenfold range. In 23 cats studied on two separate days, ventilatory measurements were correlated (r = 0.54, P less than 0.01), suggesting stable interindividual differences. Measurements during wakefulness and in anesthesia in nine cats showed that although anesthesia lowered the absolute HVR it had no influence on the range or the rank of the magnitude of the response of individuals in the group. We observed a positive correlation between ventilatory and carotid sinus nerve (CSN) responses to hypoxia measured during anesthesia in 51 cats (r = 0.63, P less than 0.001). To assess the translation of peripheral chemoreceptor activity into expiratory minute ventilation (VE) we used an index relating the increase of VE to the increase of CSN activity for a given hypoxic stimulus (delta VE/delta CSN). Comparison of this index for cats with lowest (n = 5, HVR A = 7.0 +/- 0.8) and cats with highest (n = 5, HVR A = 53.2 +/- 4.9) ventilatory responses showed similar efficiency of central translation (0.72 +/- 0.06 and 0.70 +/- 0.08, respectively). These results indicate that interindividual variation in HVR is associated with comparable variation in hypoxic sensitivity of carotid bodies. Thus differences in peripheral chemoreceptor sensitivity may contribute to interindividual variability of HVR.
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Görlach, Agnes, Gieri Camenisch, Ivica Kvietikova, Lorenz Vogt, Roland H. Wenger, and Max Gassmann. "Efficient translation of mouse hypoxia-inducible factor-1α under normoxic and hypoxic conditions." Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1493, no. 1-2 (September 2000): 125–34. http://dx.doi.org/10.1016/s0167-4781(00)00172-x.
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Dwinell, M. R., and F. L. Powell. "Chronic hypoxia enhances the phrenic nerve response to arterial chemoreceptor stimulation in anesthetized rats." Journal of Applied Physiology 87, no. 2 (August 1, 1999): 817–23. http://dx.doi.org/10.1152/jappl.1999.87.2.817.
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Chronic exposure to hypoxia results in a time-dependent increase in ventilation called ventilatory acclimatization to hypoxia. Increased O2 sensitivity of arterial chemoreceptors contributes to ventilatory acclimatization to hypoxia, but other mechanisms have also been hypothesized. We designed this experiment to determine whether central nervous system processing of peripheral chemoreceptor input is affected by chronic hypoxic exposure. The carotid sinus nerve was stimulated supramaximally at different frequencies (0.5–20 Hz, 0.2-ms duration) during recording of phrenic nerve activity in two groups of anesthetized, ventilated, vagotomized rats. In the chronically hypoxic group (7 days at 80 Torr inspired [Formula: see text]), phrenic burst frequency (fR, bursts/min) was significantly higher than in the normoxic control group with carotid sinus nerve stimulation frequencies >5 Hz. In the chronically hypoxic group, peak amplitude of integrated phrenic nerve activity ( ∫ Phr, percent baseline) or change in ∫ Phr was significantly greater at stimulation frequencies between 5 and 17 Hz, and minute phrenic activity ( ∫ Phr × fR) was significantly greater at stimulation frequencies >5 Hz. These experiments show that chronic hypoxia facilitates the translation of arterial chemoreceptor afferent input to ventilatory efferent output through a mechanism in the central nervous system.
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Frakolaki, Efseveia, Panagiota Kaimou, Maria Moraiti, Katerina Kalliampakou, Kalliopi Karampetsou, Eleni Dotsika, Panagiotis Liakos, et al. "The Role of Tissue Oxygen Tension in Dengue Virus Replication." Cells 7, no. 12 (December 1, 2018): 241. http://dx.doi.org/10.3390/cells7120241.
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Low oxygen tension exerts a profound effect on the replication of several DNA and RNA viruses. In vitro propagation of Dengue virus (DENV) has been conventionally studied under atmospheric oxygen levels despite that in vivo, the tissue microenvironment is hypoxic. Here, we compared the efficiency of DENV replication in liver cells, monocytes, and epithelial cells under hypoxic and normoxic conditions, investigated the ability of DENV to induce a hypoxia response and metabolic reprogramming and determined the underlying molecular mechanism. In DENV-infected cells, hypoxia had no effect on virus entry and RNA translation, but enhanced RNA replication. Overexpression and silencing approaches as well as chemical inhibition and energy substrate exchanging experiments showed that hypoxia-mediated enhancement of DENV replication depends on the activation of the key metabolic regulators hypoxia-inducible factors 1α/2α (HIF-1α/2α) and the serine/threonine kinase AKT. Enhanced RNA replication correlates directly with an increase in anaerobic glycolysis producing elevated ATP levels. Additionally, DENV activates HIF and anaerobic glycolysis markers. Finally, reactive oxygen species were shown to contribute, at least in part through HIF, both to the hypoxia-mediated increase of DENV replication and to virus-induced hypoxic reprogramming. These suggest that DENV manipulates hypoxia response and oxygen-dependent metabolic reprogramming for efficient viral replication.
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Hofer, Thomas, Roland H. Wenger, Marianne F. Kramer, Gloria C. Ferreira, and Max Gassmann. "Hypoxic up-regulation of erythroid 5-aminolevulinate synthase." Blood 101, no. 1 (January 1, 2003): 348–50. http://dx.doi.org/10.1182/blood-2002-03-0773.
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Abstract The erythroid-specific isoform of 5-aminolevulinate synthase (ALAS2) catalyzes the rate-limiting step in heme biosynthesis. The hypoxia-inducible factor–1 (HIF-1) transcriptionally up-regulates erythropoietin, transferrin, and transferrin receptor, leading to increased erythropoiesis and hematopoietic iron supply. To test the hypothesis that ALAS2 expression might be regulated by a similar mechanism, we exposed murine erythroleukemia cells to hypoxia (1% O2) and found an up to 3-fold up-regulation of ALAS2 mRNA levels and an increase in cellular heme content. A fragment of the ALAS2 promoter ranging from −716 to +1 conveyed hypoxia responsiveness to a heterologous luciferase reporter gene construct in transiently transfected HeLa cells. In contrast, iron depletion, known to induce HIF-1 activity but inhibit ALAS2 translation, did not increase ALAS2 promoter activity. Mutation of a previously predicted HIF-1–binding site (−323/−318) within this promoter fragment and DNA-binding assays revealed that hypoxic up-regulation is independent of this putative HIF-1 DNA-binding site.
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Langman, Sofya, Alberto Delaidelli, Yue Zhou Huang, and Poul Sorensen. "EMBR-32. INTEGRATED STRESS RESPONSE PLAYS A PRO-SURVIVAL ROLE IN MYC-DRIVEN MEDULLOBLASTOMA." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i12—i13. http://dx.doi.org/10.1093/neuonc/noab090.049.
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Abstract Medulloblastoma (MB) accounts for 20% of diagnosed brain tumors in children. Group 3 (G3) MB subtype is the most aggressive. Molecularly, G3 MB is characterized by MYC overexpression, which drives elevated mRNA translation in tumor cells. PERK is an eukaryotic translation initiation factor 2 (eIF2α) kinase that inhibits mRNA translation under endoplasmic reticulum (ER) stress conditions, such as in response to accumulation of unfolded proteins. When unfolded proteins accumulate in the ER, activated PERK phosphorylates eIF2α. This shuts down global translation and triggers integrated stress response (ISR) to help cells adapt through selective translation of mRNA encoding pro-survival proteins. High mRNA expression of PERK correlates with poor survival in G3 MB patients. In vitro, combination of ER or hypoxic stress with PERK knockdown induces apoptosis in MB cells. ISRIB is an ISR inhibitor that maintains translation rates despite eIF2α phosphorylation. Combining ISRIB with stress such as hypoxia induces apoptosis in MB cells and prevents accumulation of key ISR mediators such as ATF4. In addition, combination of ISRIB and hypoxia induces oxidative stress. Current G3 MB treatment regimens include vincristine, a known ISR inducer. Combination of ISRIB with vincristine amplifies vincristine-induced apoptosis, potentially suggesting novel therapeutic approach for MB. Our findings show that inhibition of ISR in G3 MB represents a powerful inducer of cancer cell death.
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Wen, Yang-An, Payton D. Stevens, Michael L. Gasser, Romina Andrei, and Tianyan Gao. "Downregulation of PHLPP Expression Contributes to Hypoxia-Induced Resistance to Chemotherapy in Colon Cancer Cells." Molecular and Cellular Biology 33, no. 22 (September 23, 2013): 4594–605. http://dx.doi.org/10.1128/mcb.00695-13.
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Hypoxia is a feature of solid tumors. Most tumors are at least partially hypoxic. This hypoxic environment plays a critical role in promoting resistance to anticancer drugs. PHLPP, a novel family of Ser/Thr protein phosphatases, functions as a tumor suppressor in colon cancers. Here, we show that the expression of both PHLPP isoforms is negatively regulated by hypoxia/anoxia in colon cancer cells. Interestingly, a hypoxia-induced decrease of PHLPP expression is attenuated by knocking down HIF1α but not HIF2α. Whereas the mRNA levels of PHLPP are not significantly altered by oxygen deprivation, the reduction of PHLPP expression is caused by decreased protein translation downstream of mTOR and increased degradation. Specifically, hypoxia-induced downregulation of PHLPP is partially rescued in TSC2 or 4E-BP1 knockdown cells as the result of elevated mTOR activity and protein synthesis. Moreover, oxygen deprivation destabilizes PHLPP protein by decreasing the expression of USP46, a deubiquitinase of PHLPP. Functionally, downregulation of PHLPP contributes to hypoxia-induced chemoresistance in colon cancer cells. Taken together, we have identified hypoxia as a novel mechanism by which PHLPP is downregulated in colon cancer, and the expression of PHLPP may serve as a biomarker for better understanding of chemoresistance in cancer treatment.
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Blais, Jaime D., Christina L. Addison, Robert Edge, Theresa Falls, Huijun Zhao, Kishore Wary, Costas Koumenis, et al. "Perk-Dependent Translational Regulation Promotes Tumor Cell Adaptation and Angiogenesis in Response to Hypoxic Stress." Molecular and Cellular Biology 26, no. 24 (October 9, 2006): 9517–32. http://dx.doi.org/10.1128/mcb.01145-06.
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ABSTRACT It has been well established that the tumor microenvironment can promote tumor cell adaptation and survival. However, the mechanisms that influence malignant progression have not been clearly elucidated. We have previously demonstrated that cells cultured under hypoxic/anoxic conditions and transformed cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR). Here, we show that tumors derived from K-Ras-transformed Perk−/− mouse embryonic fibroblasts (MEFs) are smaller and exhibit less angiogenesis than tumors with an intact ISR. Furthermore, Perk promotes a tumor microenvironment that favors the formation of functional microvessels. These observations were corroborated by a microarray analysis of polysome-bound RNA in aerobic and hypoxic Perk+/+ and Perk−/− MEFs. This analysis revealed that a subset of proangiogenic transcripts is preferentially translated in a Perk-dependent manner; these transcripts include VCIP, an adhesion molecule that promotes cellular adhesion, integrin binding, and capillary morphogenesis. Taken with the concomitant Perk-dependent translational induction of additional proangiogenic genes identified by our microarray analysis, this study suggests that Perk plays a role in tumor cell adaptation to hypoxic stress by regulating the translation of angiogenic factors necessary for the development of functional microvessels and further supports the contention that the Perk pathway could be an attractive target for novel antitumor modalities.
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Wouters, Bradly G., Twan van den Beucken, Michael G. Magagnin, Marianne Koritzinsky, Diane Fels, and Constantinos Koumenis. "Control of the hypoxic response through regulation of mRNA translation." Seminars in Cell & Developmental Biology 16, no. 4-5 (August 2005): 487–501. http://dx.doi.org/10.1016/j.semcdb.2005.03.009.
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Jiang, Hong, Ye Sen Zhu, Hui Xu, Yu Sun, and Qi Fang Li. "Inflammatory stimulation and hypoxia cooperatively activate HIF-1α in bronchial epithelial cells: involvement of PI3K and NF-κB." American Journal of Physiology-Lung Cellular and Molecular Physiology 298, no. 5 (May 2010): L660—L669. http://dx.doi.org/10.1152/ajplung.00394.2009.
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The transcription factor hypoxia-inducible factor (HIF)-1 plays a central physiological role in oxygen and energy homeostasis, and is activated during hypoxia by stabilization of the subunit HIF-1α. Recent studies have demonstrated that non-hypoxic stimuli can also activate HIF-1α in a cell-specific manner. Here, we demonstrate that stimulation of BEAS-2B cells and primary human bronchial epithelial cells by proinflammatory cytokines TNFα/IL-4 strongly induced expression and transcriptional activity of HIF-1α under normoxic conditions and amplified hypoxic HIF-1α activation. TNFα/IL-4 stimulated de novo HIF-1α gene transcription and translation rather than affected HIF-1α protein degradation and mRNA decay process. The activation of HIF-1α by TNFα/IL-4 was countered by the phosphoinositol 3-kinase (PI3K) inhibitor LY-294002 and rapamycin, an antagonist of mammalian target of rapamycin (mTOR), but not by inhibition of the MAPK pathway. In line, TNFα/IL-4 also activated NF-κB, whereas blocking of NF-κB by an inhibitor or silencing NF-κB subunit p65 attenuated HIF-1α activation by TNFα/IL-4. We also found the collaborative induction of VEGF, a potent angiogenic factor required for airway remodeling, by TNFα/IL-4 and hypoxia partially via HIF-1α pathway in BEAS-2B cells. This study reports the previously unsuspected collaborative regulation of HIF-1α by TNFα/IL-4 and hypoxia in bronchial epithelial cells partially via PI3K-mTOR and NF-κB pathway, and thereby will lead to the elucidation of the importance of HIF-1 in integrating inflammatory and hypoxic response in the pathogenesis of airway diseases.
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Son, Daisuke, Ichiro Kojima, Reiko Inagi, Makiko Matsumoto, Toshiro Fujita, and Masaomi Nangaku. "Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD: a proteomic analysis." American Journal of Physiology-Renal Physiology 294, no. 1 (January 2008): F62—F72. http://dx.doi.org/10.1152/ajprenal.00113.2007.
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Accumulating evidence suggests a pathogenic role of chronic hypoxia in various kidney diseases. Chronic hypoxia in the kidney was induced by unilateral renal artery stenosis, followed 7 days later by observation of tubulointerstitial injury. Proteomic analysis of the hypoxic kidney found various altered proteins. Increased proteins included lipocortin-5, calgizzarin, ezrin, and transferrin, whereas the decreased proteins were α2u-globulin PGCL1, eukaryotic translation elongation factor 1α2, and Cu/Zn superoxide dismutase (SOD1). Among these proteins, we focused on Cu/Zn-SOD, a crucial antioxidant. Western blot analysis and real-time quantitative PCR analysis confirmed the downregulation of Cu/Zn-SOD in the chronic hypoxic kidney. Furthermore, our laser capture microdissection system showed that the expression of Cu/Zn-SOD was predominant in the tubulointerstitium and was decreased by chronic hypoxia. The tubulointerstitial injury estimated by histology and immunohistochemical markers was ameliorated by tempol, a SOD mimetic. This amelioration was associated with a decrease in levels of the oxidative stress markers 4-hydroxyl-2-nonenal and nitrotyrosine. Our in vitro studies utilizing cultured tubular cells revealed a role of TNF-α in downregulation of Cu/Zn-SOD. Since the administration of anti-TNF-α antibody ameliorated Cu/Zn-SOD suppression, TNF-α seems to be one of the suppressants of Cu/Zn-SOD. In conclusion, our proteomic analysis revealed a decrease in Cu/Zn-SOD, at least partly by TNF-α, in the chronic hypoxic kidney. This study, for the first time, uncovered maladaptive suppression of Cu/Zn-SOD as a mediator of a vicious cycle of oxidative stress and subsequent renal injury induced by chronic hypoxia.
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Robichaud, A., K. Attwood, A. Balgi, M. Roberge, and A. Weeks. "P.042 Raloxifene sensitizes glioblastoma cells to hypoxia-induced death through inhibition of stress granule dissolution." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 45, s2 (June 2018): S27. http://dx.doi.org/10.1017/cjn.2018.144.
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Background: Glioblastoma (GBM) is the most common primary malignant brain tumour. Despite aggressive therapy, median survival is only 14 months. Death typically results from treatment failure and local recurrence. The GBM microenvironment is highly hypoxic, which correlates with treatment resistance. Cytoplasmic RNA stress granules (SGs) form in response to hypoxic stress and act as sights of mRNA triage, allowing preferential translation of pro-survival mRNA during stress. We hypothesize that SGs may play a role in hypoxia-induced resistance to therapy, and may be targetable by chemotherapeutics to improve outcomes. Methods: We screened 1280 approved compounds to identify drugs that inhibited formation or dissolution of SGs in U251 glioma cells. Raloxifene inhibited SG dissolution in a dose dependent manner. We treated cells with raloxifene and incubated them in hypoxia, and then measured rates of cell death using cell counting and Presto blue. Results: Cell death rates were synergistically higher in cells treated with the combination of raloxifene and hypoxia compared to either treatment alone. Conclusions: Raloxifene inhibits the dissolution of SGs in glioma cells, and combination treatment results in synergistic tumour cell death. Taken together, this provides evidence that inhibition of SG dissolution may be a viable target for future GBM chemotherapeutics.
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Corroyer-Dulmont, Aurélien, Elodie A. Pérès, Edwige Petit, Lucile Durand, Léna Marteau, Jérôme Toutain, Didier Divoux, et al. "Noninvasive assessment of hypoxia with 3-[18F]-fluoro-1-(2-nitro-1-imidazolyl)-2-propanol ([18F]-FMISO): a PET study in two experimental models of human glioma." Biological Chemistry 394, no. 4 (April 1, 2013): 529–39. http://dx.doi.org/10.1515/hsz-2012-0318.
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Abstract Despite multiple advances in cancer therapies, patients with glioblastoma (GBM) still have a poor prognosis. Numerous glioma models are used not only for the development of innovative therapies but also to optimize conventional ones. Given the significance of hypoxia in drug and radiation resistance and that hypoxia is widely observed among GBM, the establishment of a reliable method to map hypoxia in preclinical human models may contribute to the discovery and translation of future and more targeted therapies. The aim of this study was to compare the hypoxic status of two commonly used human orthotopic glioma models (U87 and U251) developed in rats and studied by noninvasive hypoxia imaging with 3-[18F]fluoro-1-(2-nitro-1-imidazolyl)-2-propanol-micro-positron emission tomography ([18F]-FMISO-μPET). In parallel, because of the relationships between angiogenesis and hypoxia, we used magnetic resonance imaging (MRI), histology, and immunohistochemistry to characterize the tumoral vasculature. Although all tumors were detectable in T2-weighted MRI and 2-deoxy-2-[18F]fluoro-d-glucose-μPET, only the U251 model exhibited [18F]-FMISO uptake. Additionally, the U251 tumors were less densely vascularized than U87 tumors. Our study demonstrates the benefits of noninvasive imaging of hypoxia in preclinical models to define the most reliable one for translation of future therapies to clinic based on the importance of intratumoral oxygen tension for the efficacy of chemotherapy and radiotherapy.
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Ouyang, Weiming, Chikako Torigoe, Hui Fang, Tao Xie, and David M. Frucht. "Anthrax Lethal Toxin Inhibits Translation of Hypoxia-inducible Factor 1α and Causes Decreased Tolerance to Hypoxic Stress." Journal of Biological Chemistry 289, no. 7 (December 23, 2013): 4180–90. http://dx.doi.org/10.1074/jbc.m113.530006.
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Connolly, Eileen, Steve Braunstein, Silvia Formenti, and Robert J. Schneider. "Hypoxia Inhibits Protein Synthesis through a 4E-BP1 and Elongation Factor 2 Kinase Pathway Controlled by mTOR and Uncoupled in Breast Cancer Cells." Molecular and Cellular Biology 26, no. 10 (May 15, 2006): 3955–65. http://dx.doi.org/10.1128/mcb.26.10.3955-3965.2006.
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ABSTRACT Hypoxia is a state of low oxygen availability that limits tumor growth. The mechanism of protein synthesis inhibition by hypoxia and its circumvention by transformation are not well understood. Hypoxic breast epithelial cells are shown to downregulate protein synthesis by inhibition of the kinase mTOR, which suppresses mRNA translation through a novel mechanism mitigated in transformed cells: disruption of proteasome-targeted degradation of eukaryotic elongation factor 2 (eEF2) kinase and activation of the regulatory protein 4E-BP1. In transformed breast epithelial cells under hypoxia, the mTOR and S6 kinases are constitutively activated and the mTOR negative regulator tuberous sclerosis complex 2 (TSC2) protein fails to function. Gene silencing of 4E-BP1 and eEF2 kinase or TSC2 confers resistance to hypoxia inhibition of protein synthesis in immortalized breast epithelial cells. Breast cancer cells therefore acquire resistance to hypoxia by uncoupling oxygen-responsive signaling pathways from mTOR function, eliminating inhibition of protein synthesis mediated by 4E-BP1 and eEF2.
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Jean, Didier, Nathalie Rousselet, and Raymond Frade. "Cathepsin L expression is up-regulated by hypoxia in human melanoma cells: role of its 5′-untranslated region." Biochemical Journal 413, no. 1 (June 12, 2008): 125–34. http://dx.doi.org/10.1042/bj20071255.
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Overexpression of cathepsin L, a cysteine protease, and consequently procathepsin L secretion switch the phenotype of human melanoma cells to highly tumorigenic and strongly metastatic. This led us to identify the DNA regulatory sequences involved in the regulation of cathepsin L expression in highly metastatic human melanoma cells. The results of the present study demonstrated the presence of regulatory sequences in the 3′ region downstream of the cathepsin L gene and in the 3′- and 5′-flanking regions of GC/CCAAT sites of its promoter. In addition, we established that the 5′-UTR (untranslated region) was the most important region for cathepsin L expression. This 5′-UTR integrated an alternative promoter and sequences involved in post-transcriptional regulation. Transfection experiments of bicistronic reporter vectors and RNAs demonstrated that the cathepsin L 5′-UTR contained a functional IRES (internal ribosome entry site). This complete IRES was present only in one of the three splice variants, which differed in their 5′-UTR. Then, we analysed cathepsin L expression in this human melanoma cell line grown under hypoxia. We demonstrated that under moderate hypoxic conditions (1% O2) intracellular expression of cathepsin L was up-regulated. Hypoxia significantly increased only the expression of the transcript which contains the complete IRES, but inhibited promoter activity. These results suggest that the presence of an IRES allowed cathepsin L mRNA translation to be efficient under hypoxic conditions. Altogether, our results indicated that in vivo a tumour hypoxic environment up-regulates cathepsin L expression which promotes tumour progression.
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Erler, Janine T., Christopher J. Cawthorne, Kaye J. Williams, Marianne Koritzinsky, Bradley G. Wouters, Clare Wilson, Crispin Miller, Costas Demonacos, Ian J. Stratford, and Caroline Dive. "Hypoxia-Mediated Down-Regulation of Bid and Bax in Tumors Occurs via Hypoxia-Inducible Factor 1-Dependent and -Independent Mechanisms and Contributes to Drug Resistance." Molecular and Cellular Biology 24, no. 7 (April 1, 2004): 2875–89. http://dx.doi.org/10.1128/mcb.24.7.2875-2889.2004.
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ABSTRACT Solid tumors with disorganized, insufficient blood supply contain hypoxic cells that are resistant to radiotherapy and chemotherapy. Drug resistance, an obstacle to curative treatment of solid tumors, can occur via suppression of apoptosis, a process controlled by pro- and antiapoptotic members of the Bcl-2 protein family. Oxygen deprivation of human colon cancer cells in vitro provoked decreased mRNA and protein levels of proapoptotic Bid and Bad. Hypoxia-inducible factor 1 (HIF-1) was dispensable for the down-regulation of Bad but required for that of Bid, consistent with the binding of HIF-1α to a hypoxia-responsive element (positions −8484 to −8475) in the bid promoter. Oxygen deprivation resulted in proteosome-independent decreased expression of Bax in vitro, consistent with a reduction in global translation efficiency. The physiological relevance of Bid and Bax down-regulation was confirmed in tumors in vivo. Oxygen deprivation resulted in decreased drug-induced apoptosis and clonogenic resistance to agents with different mechanisms of action. The contribution of Bid and/or Bax down-regulation to drug responsiveness was demonstrated by the relative resistance of normoxic cells that had no or reduced expression of Bid and/or Bax and by the finding that forced expression of Bid in hypoxic cells resulted in increased sensitivity to the topoisomerase II inhibitor etoposide.
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Garziera, Marica, Lucia Scarabel, and Giuseppe Toffoli. "Hypoxic Modulation of HLA-G Expression through the Metabolic Sensor HIF-1 in Human Cancer Cells." Journal of Immunology Research 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/4587520.
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The human leukocyte antigen-G (HLA-G) is considered an immune checkpoint molecule involved in tumor immune evasion. Hypoxia and the metabolic sensor hypoxia-inducible factor 1 (HIF-1) are hallmarks of metastasization, angiogenesis, and intense tumor metabolic activity. The purpose of this review was to examine original in vitro studies carried out in human cancer cell lines, which reported data about HLA-G expression and HIF-1 mediated-HLA-G expression in response to hypoxia. The impact of HLA-G genomic variability on the hypoxia responsive elements (HREs) specific for HIF-1 binding was also discussed. Under hypoxia, HLA-G-negative cell lines might transcribe HLA-G without translation of the protein while in contrast, HLA-G-positive cell lines, showed a reduced HLA-G transcriptional activity and protein level. HIF-1 modulation of HLA-G expression induced by hypoxia was demonstrated in different cell lines. HLA-G SNPs rs1632947 and rs41551813 located in distinct HREs demonstrated a prominent role of HIF-1 binding by DNA looping. Our research revealed a fine regulation of HLA-G in hypoxic conditions through HIF-1, depending on the cellular type and HLA-G genomic variability. Specifically, SNPs found in HREs should be considered in future investigations as markers with potential clinical value especially in metastatic malignancies.
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Tabe, Yoko, Linhua Jin, Takashi Miida, Michael Andreeff, and Marina Konopleva. "Growth-Inhibitory Effects of a Class I PI3K Inhibitor GDC-0941 Are Modulated by Hypoxia-Induced mTOR Pathway Activation in Mantle Cell Lymphoma." Blood 118, no. 21 (November 18, 2011): 1424. http://dx.doi.org/10.1182/blood.v118.21.1424.1424.
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Abstract Abstract 1424 Hypoxia confers pro-survival signals to tumor cells via multiple mechanisms including activation of phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway. Constitutive activation of PI3K/Akt signaling pathway is documented in aggressive blastoid variants of mantle cell lymphoma (MCL) and is implicated in the pathogenesis of MCL. mTOR signaling, one of the important downstream targets of Akt, positively regulates protein translation by phosphorylating p70 ribosomal S6 kinase (S6K) or eukaryotic initiation factor 4E-binding protein-1 (4E-BP1). We have reported that the Class IA PI3K isoforms, mainly p110α and partially p110δ, are responsible for PI3K/Akt/mTOR signaling activation in blastoid MCL cells (Zhou et al., ASH abstract 2010). In this study, the activity and molecular mechanisms of action of a selective pan-isoform class I PI3K inhibitor GDC-0941 (Genentech) were investigated in the context of hypoxic microenvironment in MCL cells. For hypoxia experiments, MCL cells were cultured under 1% O2 for at least 14 days to assure their sustained proliferation and survival. Under hypoxia, more cells accumulated in G0/G1 phase, indicating that hypoxic conditions promote cell cycle quiescence in MCL cells. GDC-0941 treatment in normoxia resulted in a reduction of cell proliferation in a dose-dependent manner (IC50 at 48 hrs; 0.7 μM for Granta519, 0.5 μM for JVM2, 1.0 μM for MINO, 0.7 μM for Jeko-1, MTT test). In hypoxia, higher doses of GDC-0941 were required to cause cell growth inhibition compared to normoxic conditions in Granta519 (IC50; 1.7 μM), JVM2 (3.5 μM) and MINO (1.2 μM). Further, GDC-0941 failed to inhibit growth of Jeko-1 cells under hypoxia. GDC-0941 (0.5 μM) induced G0/1 cell cycle arrest under both normoxic and hypoxic conditions in Granta519, JVM2 and MINO cells. No significant induction of apoptosis by GDC-0941 (0.5 μM) was observed in any of the tested MCL cells. GDC-0941 completely inhibited phosphorylated (p-Ser473) Akt in all cell lines analyzed under both normoxic and hypoxic conditions, which resulted in decreased expression of p-GSK-3β and its downstream target cyclin D1. GDC-0941 further downregulated the mTOR downstream targets p-S6K and p-4EBP1 in Granta519, JVM2 and MINO cells under both, normoxia and hypoxia. On the contrary, GDC-0941 failed to affect hypoxia-induced p-S6K and p-4EBP1 expression levels in Jeko-1 cells, whereas potently suppressed these proteins at ambient oxygen level. These results suggest that in Jeko-1 cells hypoxia activates mTOR through PI3K-independent pathways. To test this, we examined consequences of mTOR blockade in Jeko-1 cells. mTOR inhibitor rapamycin (100 nM) moderately diminished cell growth under normoxic conditions causing accumulation of cells in G0/1 cell cycle phase but no apoptosis. In turn, under hypoxia rapamycin profoundly inhibited cell growth, inducing >80% of MCL cells to undergo cell death. These findings indicate that in certain MCL cells hypoxia activates mTOR through alternative, PI3K-independent pathways, which facilitate cell survival under hypoxia. Hence, blockade of class I PI3K may eliminate circulating MCL cells but not tissue-resident cells in hypoxic areas of the bone marrow or lymph nodes. In turn, simultaneous therapeutic ablation of PI3K/Akt and mTOR pathway may represent a promising strategy to target the aggressive blastoid variants of MCL cells in the hypoxic microenvironments. Disclosures: No relevant conflicts of interest to declare.
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Shih, Chun-Yan, Pei-Ting Wang, Wu-Chou Su, Hsisheng Teng, and Wei-Lun Huang. "Nanomedicine-Based Strategies Assisting Photodynamic Therapy for Hypoxic Tumors: State-of-the-Art Approaches and Emerging Trends." Biomedicines 9, no. 2 (February 1, 2021): 137. http://dx.doi.org/10.3390/biomedicines9020137.
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Since the first clinical cancer treatment in 1978, photodynamic therapy (PDT) technologies have been largely improved and approved for clinical usage in various cancers. Due to the oxygen-dependent nature, the application of PDT is still limited by hypoxia in tumor tissues. Thus, the development of effective strategies for manipulating hypoxia and improving the effectiveness of PDT is one of the most important area in PDT field. Recently, emerging nanotechnology has benefitted progress in many areas, including PDT. In this review, after briefly introducing the mechanisms of PDT and hypoxia, as well as basic knowledge about nanomedicines, we will discuss the state of the art of nanomedicine-based approaches for assisting PDT for treating hypoxic tumors, mainly based on oxygen replenishing strategies and the oxygen dependency diminishing strategies. Among these strategies, we will emphasize emerging trends about the use of nanoscale metal–organic framework (nMOF) materials and the combination of PDT with immunotherapy. We further discuss future perspectives and challenges associated with these trends in both the aspects of mechanism and clinical translation.
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Koritzinsky, Marianne, Renaud Seigneuric, Michaël G. Magagnin, Twan van den Beucken, Philippe Lambin, and Bradly G. Wouters. "The hypoxic proteome is influenced by gene-specific changes in mRNA translation." Radiotherapy and Oncology 76, no. 2 (August 2005): 177–86. http://dx.doi.org/10.1016/j.radonc.2005.06.036.
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Chen, Mo-Xian, Fu-Yuan Zhu, Feng-Zhu Wang, Neng-Hui Ye, Bei Gao, Xi Chen, Shan-Shan Zhao, et al. "Alternative splicing and translation play important roles in hypoxic germination in rice." Journal of Experimental Botany 70, no. 3 (December 10, 2018): 817–33. http://dx.doi.org/10.1093/jxb/ery393.
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Wouters, B. G., M. Koritzinsky, M. Magagnin, T. van den Beucken, C. Koumenis, and P. Lambin. "9 Hypoxic regulation of translation initiation and its impact on gene expression." Radiotherapy and Oncology 78 (March 2006): S4. http://dx.doi.org/10.1016/s0167-8140(06)80503-7.
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Longo, LD, and S. Packianathan. "Acute hypoxia induces elevation of ornithine decarboxylase activity in neonatal rat brain slices." Reproduction, Fertility and Development 7, no. 3 (1995): 385. http://dx.doi.org/10.1071/rd9950385.
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Recent studies in vivo have demonstrated that ornithine decarboxylase (ODC) activity in the fetal rat brain is elevated 4-5-fold by acute maternal hypoxia. This hypoxic-associated increase is seen in the rat brain in both the newborn and the adult. Because of the intimate involvement of ODC in transcription and translation, as well as in growth and development, it is imperative that the manner in which hypoxia affects the regulation of this enzyme be better understood. In order to achieve this, a brain preparation in vitro was required to eliminate the confounding effects of the dam on the fetal and newborn brain ODC activity in vivo. Therefore, brain slices from 3-4-day-old (P-3) newborn rats were utilized to test the hypothesis that ODC activity increases in response to hypoxia in vitro. Cerebral slices from the P-3 rat pups were allowed to equilibrate and recover in artificial cerebrospinal fluid (ACSF) continuously bubbled with a mixture of 95% O2 and 5% CO2 for 1 h before beginning hypoxic exposures. Higher basal ODC activities were obtained by treating the slices with 0.03% fetal bovine serum (FBS) and 0.003% bovine serum albumin (BSA), rather than with ACSF alone. Hypoxia was induced in the slices by replacing the gas with 40%, 21%, 10%, or 5% O2, all with 5% CO2 and balance N2. With FBS and BSA treatment, ODC activity was maintained at about 0.15-0.11 nM CO2 mg-1 protein h-1 throughout the experiment, which was 2-3-fold higher than that without FBS and BSA. ODC activity increased significantly and peaked between 1 h and 2 h after initiation of hypoxia. For instance, with 21% O2, ODC activity increased approximately 1.5-fold at 1 h and approximately 2-fold at 2 h. These studies demonstrate that: (1) the hypoxic-induced increases observed in vivo in the fetal and newborn rat brain ODC activity can be approximated in a newborn rat brain slice preparation in vitro; (2) newborn rat brain slice preparations may provide an alternative to methods in vivo or cell culture methods for studying the regulation of acute hypoxic-induced enzymes; and (3) high, stable baseline ODC activities in brain slices suggest that the cells in the slice are capable of active metabolism if FBS and BSA are available to mimic conditions in vivo.
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Schranzhofer, Matthias, Manfred Schifrer, Prem Ponka, and Ernst W. Muellner. "Modulation of IRP Binding Activity by Oxygen in Primary Erythroid Cells." Blood 110, no. 11 (November 16, 2007): 2662. http://dx.doi.org/10.1182/blood.v110.11.2662.2662.
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Abstract Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are cytoplasmic RNA-binding proteins that target specific stem-loop RNA structures known as iron responsive elements (IRE). Binding of IRPs to IREs inhibits translation of ferritin mRNA and stabilizes transferrin receptor (TfR) mRNA. Various factors have been reported to regulate binding activity of IRPs, such as iron, phosphorylation, nitric oxide and hypoxia. While there is a consistent agreement on the negative effect of iron on the interaction between IRPs and IREs, reports regarding the influence of hypoxia on the IRE-binding activity of IRPs vary in a species and cell specific manner. It was the aim of this work to study the effect of hypoxic (3% oxygen) and normoxic (20% oxygen) conditions on IRP binding activity in primary erythroid cells. The cells were induced for differentiation and incubated under physiological, low (Desferrioxamine) and high (ferric ammonium citrate) iron conditions. Binding activity of IRPs and protein levels of ferritin and TfR as well as cell proliferation and differentiation parameters were determined to analyze the regulation of iron metabolism during terminal differentiation. The data show, that in developing red blood cells binding activities of IRP1 and IRP2 are reduced at 3% oxygen. This reduction correlates with increased ferritin protein levels and decreased TfR protein levels. Moreover, incubation under hypoxia strongly decreased cell expansion and reduces hemoglobinization. These results suggest that terminal erythroid differentiation in the bone marrow might occur under normoxic rather than hypoxic conditions.
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Millet, Grégoire P., and Kilian Jornet. "On Top to the Top—Acclimatization Strategy for the “Fastest Known Time” to Mount Everest." International Journal of Sports Physiology and Performance 14, no. 10 (November 1, 2019): 1438–41. http://dx.doi.org/10.1123/ijspp.2018-0931.
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Purpose: To present the acclimatization strategy employed by an elite athlete prior to 2 successful ascents to Mount Everest (including a “fastest known time”) in 1 wk. Methods: Training volume, training content, and altitude exposure were recorded daily. Vertical velocity was recorded by GPS (global positioning system) heart-rate monitor. Results: The subject first used a live high–train low and high preacclimatization method in normobaric hypoxia (NH). Daily, he combined sleeping in a hypoxic tent (total hours: ∼260) and exercising “as usual” in normoxia but also in NH (altitude >6000 m: 30 h), including at high intensity. The hypoxic sessions were performed at the second threshold on treadmill in NH at 6000 m, and the pulse saturation increased from 70% to 85% over 1 mo. Then, the subject was progressively exposed to hypobaric hypoxia, first in the Alps and then in the Himalayas. On day 18, he reached for the second time an altitude >8000 m with the fastest vertical velocity (350 m/h) ever measured between 6300 and 8400 m. Afterward, he climbed twice in a week to the summit of Mount Everest (8848 m, including a “fastest known time” of 26.5 h from Rongbuk Monastery, 5100 m). Conclusion: Overall, this acclimatization was successful and in line with the most recent recommendations: first, using live high–train low and high, and second, using hypobaric hypoxia at increasing altitudes for a better translation of the NH benefits to hypobaric hypoxia. This case study reports the preparation for the most outstanding performance ever acheived at an extreme altitude.
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Han, Kyung Seok, Na Li, Peter A. Raven, Estelle Li, Ladan Fazli, Martin E. Gleave, and Alan I. So. "ER stress protein GRP78 as a therapeutic target combined with antiangiogenic therapy in renal cell carcinoma." Journal of Clinical Oncology 31, no. 6_suppl (February 20, 2013): 428. http://dx.doi.org/10.1200/jco.2013.31.6_suppl.428.
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428 Background: Antiangiogenic therapy deprives oxygen and nutrition from the tumor. These stresses cause unfolded proteins in tumor cells. Glucose regulated protein 78 (GRP78) binds to unfolded proteins and its subsequent activation suppresses global mRNA translation to protect cells from excessive unfolded proteins. We investigated a potential role of GRP78 as a combined therapeutic target in renal cell carcinoma treated with antiangiogenic therapy. Methods: Renal cell carcinoma cells (Caki-1, Caki-2, UMRC-3, and UMRC-6) were used to investigate the effect of GRP78 knockdown, which was performed by small interfering RNA. Caki-1 xenografts were developed and treated with sunitinib 40mg/kg/day to evaluate in vivo expression of GRP78 during antiangiogenic therapy. Caki-1 cells stably overexpressing GRP78 were developed to investigate the role of GRP78 in cancer cell. Hypoxic stress was induced by 1% hypoxia chamber and hypoglycaemic stress was induced by glucose-free media. Downstream signalling pathways of GRP78 were evaluated by Western blots. Results: In vitro hypoxia and/or glucose deprivation induced GRP78 upregulation in Caki-1 cells. GRP78 was also induced in Caki-1 xenografts treated by sunitinib. Overexpression of GRP78 increased tumor proliferation in hypoxic and/or hypoglycemic stresses by activating PERK/eIF2α pathway and protected tumor cells from stress-induced apoptosis. Knockdown of GRP78 using small interference RNA inhibited cancer cell survival and induced apoptosis in renal cell carcinoma cells in vitro. GRP78 knockdown also sensitized renal cell carcinoma cells to ER stress-induced apoptosis and hypoxic and hypoplycemic stress-induces apoptosis. Conclusions: Antiangiogenic therapy induces ER stress by depriving oxygen and glucose from renal cell carcinoma. ER protein GRP78 has a critical role in protecting renal cell carcinoma cells from hypoxic and hypoglycemic stress induced by antiangiogenic therapy. Knockdown of GRP78 sensitizes RCC cells to apoptotic cell death from anti-angiogenic stresses. Our results suggest that GRP78 is a novel therapeutic target in renal cell carcinoma management.
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Basu, Rajit K., Susan Hubchak, Tomoko Hayashida, Constance E. Runyan, Paul T. Schumacker, and H. William Schnaper. "Interdependence of HIF-1α and TGF-β/Smad3 signaling in normoxic and hypoxic renal epithelial cell collagen expression." American Journal of Physiology-Renal Physiology 300, no. 4 (April 2011): F898—F905. http://dx.doi.org/10.1152/ajprenal.00335.2010.
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Increasing evidence suggests that chronic kidney disease may develop following acute kidney injury and that this may be due, in part, to hypoxia-related phenomena. Hypoxia-inducible factor (HIF) is stabilized in hypoxic conditions and regulates multiple signaling pathways that could contribute to renal fibrosis. As transforming growth factor (TGF)-β is known to mediate renal fibrosis, we proposed a profibrotic role for cross talk between the TGF-β1 and HIF-1α signaling pathways in kidney cells. Hypoxic incubation increased HIF-1α protein expression in cultured human renal tubular epithelial cells and mouse embryonic fibroblasts. TGF-β1 treatment further increased HIF-1α expression in cells treated with hypoxia and also increased HIF-1α in normoxic conditions. TGF-β1 did not increase HIF-1α mRNA levels nor decrease the rate of protein degradation, suggesting that it enhances normoxic HIF-1α translation. TGF-β receptor (ALK5) kinase activity was required for increased HIF-1α expression in response to TGF-β1, but not to hypoxia. A dominant negative Smad3 decreased the TGF-β-stimulated reporter activity of a HIF-1α-sensitive hypoxia response element. Conversely, a dominant negative HIF-1α construct decreased Smad-binding element promoter activity in response to TGF-β. Finally, blocking HIF-1α transcription with a biochemical inhibitor, a dominant negative construct, or gene-specific knockdown decreased basal and TGF-β1-stimulated type I collagen expression, while HIF-1α overexpression increased both. Taken together, our data demonstrate cooperation in signaling between Smad3 and HIF-1α and suggest a new paradigm in which HIF-1α is necessary for normoxic, TGF-β1-stimulated renal cell fibrogenesis.
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Choi, Jeong Hae, Hyun Kook Cho, Yung Hyun Choi, and JaeHun Cheong. "Activating transcription factor 2 increases transactivation and protein stability of hypoxia-inducible factor 1α in hepatocytes." Biochemical Journal 424, no. 2 (November 11, 2009): 285–96. http://dx.doi.org/10.1042/bj20090371.
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HIF-1 (hypoxia inducible factor 1) performs a crucial role in mediating the response to hypoxia. However, other transcription factors are also capable of regulating hypoxia-induced target-gene transcription. In a previous report, we demonstrated that the transcription factor ATF-2 (activating transcription factor 2) regulates hypoxia-induced gene transcription, along with HIF-1α. In the present study, we show that the protein stability of ATF-2 is induced by hypoxia and the hypoxia-mimic CoCl2 (cobalt chloride), and that ATF-2 induction enhances HIF-1α protein stability via direct protein interaction. The knockdown of ATF-2 using small interfering RNA and translation-inhibition experiments demonstrated that ATF-2 plays a key role in the maintenance of the expression level and transcriptional activity of HIF-1α. Furthermore, we determined that ATF-2 interacts directly with HIF-1α both in vivo and in vitro and competes with the tumour suppressor protein p53 for HIF-1α binding. Collectively, these results show that protein stabilization of ATF-2 under hypoxic conditions is required for the induction of the protein stability and transactivation activity of HIF-1α for efficient hypoxia-associated gene expression.
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Huelsemann, Malte, Lukas P. Frenzel, Dunja Baatout, Julia Claasen, Sebastian Theurich, Laurent Kintzelé, Hans Jiro Becker, et al. "Impact of Hypoxia As Novel Microenvironmental Factor On Drug Susceptibility of Primary CLL Cells." Blood 120, no. 21 (November 16, 2012): 3918. http://dx.doi.org/10.1182/blood.v120.21.3918.3918.
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Abstract Abstract 3918 Background: CLL cells circulating in the peripheral blood are sensitive to therapy while malignant cells residing in the microenvironment survive and are the source of relapse. One of the strongest microenvironmental stimuli is CD40 ligand (CD40L)-CD40 interaction, which induces proliferative/anti-apoptotic genes in CLL cells, protecting them from apoptosis and many cytotoxic drugs. Despite the evident importance of CD40 activation further stimuli have to be considered, especially hypoxia. Lymph nodes, particularly those being infiltrated by malignant cells, show a low oxygen tension (<1%). Prior CLL investigations never took this important factor into account, hence the impact of hypoxia on cell survival and drug-resistance is still unrevealed. Methods: We have established an in vitro model, which mimics hypoxic conditions and CD40L-CD40 interaction, in order to understand the molecular basis of drug resistance of CLL cells resident in the microenvironment. CLL cells were cultured on CD40L feeder cells and kept up to 96 hours in hypoxia (1% O2) or normoxia (21% O2). We determined how proliferation rates in CLL are affected by these conditions and subsequently applied several drugs to investigate differences in drug efficacy between normoxia and hypoxia. Apoptosis was determined by AnnexinV/7AAD-staining and subsequent flow cytometry. Expression of potential target molecules was determined by qRT-PCR and Western Blotting. Results: Hypoxia is known to protect malignant cells in solid cancers from chemotherapy. We made similar observations, since classical DNA-targeting drugs were inefficient to kill CLL cells under hypoxic conditions. However, we identified ABT-737, which affects mitochondrial integrity, to be even more efficient under hypoxic conditions compared to normoxia. In order to explain this discrepancy we investigated the expression of several mitochondrial localized anti-/proapoptotic genes on RNA and protein level. We show that the de-regulation of BclXL and Mcl-1 under hypoxic conditions is essential for ABT-737 sensitivity. BclXL deregulation depends on a general reduction in protein translation in hypoxic cells. Mcl-1 protein expression differs from its mRNA expression, hence we expected regulation subsequent to protein synthesis. Indeed we could identify an increased activity of the proteasome in hypoxia, as Mcl-1 is a short-lived protein with a rapid proteasomal turnover this is a feasible explanation for the observed downregulation. Interestingly, hypoxia has a great impact on proliferation of primary CLL cells under different stimuli in vitro. Conclusion: These are the first experiments investigating the impact of oxygen tension on survival and response to chemotherapy of CLL cells. We show that hypoxia renders CLL cells resistant to classical DNA-targeting agent Fludarabine and Bendamustine. Furthermore we point out that small molecules like ABT-737, which specifically target mitochondria, might be efficient in targeting CLL cells protected by hypoxia and CD40L-CD40 interaction within the microenvironment. Development of novel in vitro models like ours will help us understand the specific molecular changes induced by microenvironmental stimuli and their impact on drug efficacy. These findings will allow us to identify novel therapeutic targets. M.Hu. and L.P.F. contributed equally to this work Disclosures: No relevant conflicts of interest to declare.
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Botting, K. J., K. L. Skeffington, Y. Niu, B. J. Allison, K. L. Brain, N. Itani, C. Beck, et al. "Translatable mitochondria-targeted protection against programmed cardiovascular dysfunction." Science Advances 6, no. 34 (August 2020): eabb1929. http://dx.doi.org/10.1126/sciadv.abb1929.
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The prenatal origins of heart disease in offspring have been established. However, research in species with developmental milestones comparable to humans is lacking, preventing translation of this knowledge to clinical contexts. Using sheep and chickens, two species with similar cardiovascular developmental milestones to humans, we combined in vivo experiments with in vitro studies at organ, cellular, mitochondrial, and molecular levels. We tested mitochondria-targeted antioxidant intervention with MitoQ against cardiovascular dysfunction programmed by developmental hypoxia, a common complication in human pregnancy. Experiments in sheep determined in vivo fetal and adult cardiovascular function through surgical techniques not possible in humans, while those in chicken embryos isolated effects independent of maternal or placental influences. We show that hypoxia generates mitochondria-derived oxidative stress during cardiovascular development, programming endothelial dysfunction and hypertension in adult offspring. MitoQ treatment during hypoxic development protects against this cardiovascular risk via enhanced nitric oxide signaling, offering a plausible intervention strategy.
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Li, Wen, Yue Yang, Zhaoyu Ba, Shupeng Li, Hao Chen, Xiaoyan Hou, Linlin Ma, et al. "MicroRNA-93 Regulates Hypoxia-Induced Autophagy by Targeting ULK1." Oxidative Medicine and Cellular Longevity 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/2709053.
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The expression of the core autophagy kinase, Unc51-like kinase 1 (ULK1), is regulated transcriptionally and translationally by starvation-induced autophagy. However, how ULK1 is regulated during hypoxia is not well understood. Previously, we showed that ULK1 expression is induced by hypoxia stress. Here, we report a new ULK1-modulating microRNA, miR-93; its transcription is negatively correlated with the translation of ULK1 under hypoxic condition. miR-93 targets ULK1 and reduces its protein levels under hypoxia condition. miR-93 also inhibits hypoxia-induced autophagy by preventing LC3-I to LC3-II transition and P62 degradation; these processes are reversed by the overexpression of an endogenous miR-93 inhibitor. Re-expression of ULK1 without miR-93 response elements restores the hypoxia-induced autophagy which is inhibited by miR-93. Finally, we detected the effects of miR-93 on cell viability and apoptosis in noncancer cell lines and cancer cells. We found that miR-93 sustains the viability of MEFs (mouse embryonic fibroblasts) and inhibits its apoptosis under hypoxia. Thus, we conclude that miR-93 is involved in hypoxia-induced autophagy by regulating ULK1. Our results provide a new angle to understand the complicated regulation of the key autophagy kinase ULK1 during different stress conditions.
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Gardner, Lawrence B. "Inhibition of Nonsense Mediated RNA Decay in Hypoxic Cells; Implications for Thalassemia." Blood 110, no. 11 (November 16, 2007): 1781. http://dx.doi.org/10.1182/blood.v110.11.1781.1781.
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Abstract Several common β globin gene mutations found in thalassemia are thought to promote rapid degradation of the aberrant mRNA through a specific mechanism termed nonsense mediated RNA decay (NMD). NMD, elicited through mutations leading to premature termination codons, is thought to be responsible not only for the degradation of the β globin PTC 39 mutation, responsible for >90% of thalassemia in Sardinia, but also for the degradation of 30% of all known human mutations and up to 10% of the genome. However, because NMD has been thought of as a constitutive and not a regulated pathway, the potential role of NMD in the dynamic regulation of gene expression has not been well explored. We have determined that NMD is inhibited in hypoxic cells. This hypoxic inhibition of NMD significantly prolongs the half-life of multiple mRNAs degraded by NMD, including the β globin PTC 39 mutation. We have also identified several additional mRNAs whose stabilities are significantly (>2 fold) 1. Increased when Rent1, an RNA helicase necessary for NMD is silenced 2. Decreased when Rent1 is over-expressed and 3. Increased in hypoxic cells when NMD is inhibited. These include the mRNAs that are integral for the cellular response to multiple stresses found in thalassemia, including hypoxic stress. Indeed, we observed that the cellular stress response is augmented when NMD is inhibited. The central component for many cellular stress responses is the phosphorylation of a translation factor, eIF2α. We and others have demonstrated that eIF2α is phosphorylated in hypoxic cells via the kinase PERK. Phosphorylation of eIF2α leads to the suppression of protein synthesis and the translational and transcriptional up-regulation of stress response genes. We hypothesized that phosphorylation of eIF2α was also responsible for the hypoxic inhibition of NMD. Indeed, when we used cells generated from mice in which wild-type eIF2α has been replaced by an eIF2α that cannot be phosphorylated, we found that hypoxic inhibition of NMD did not occur, demonstrating that is eIF2α phosphorylation is necessary for hypoxic inhibition of NMD. Degradation of NMD targets occurs in cytoplasmic processing bodies, which contain many of the enzymes necessary for mRNA catabolism. We noted that a distinct type of mRNA containing body, termed stress bodies, which do not have the capacity for RNA decay, are induced in hypoxic cells. This formation is dependent on PERK phosphorylation of eIF2α. While there are several potential mechanism by which hypoxic phosphorylation of eIF2α could inhibit NMD, our preliminary data suggests a model in which NMD targets are sequestered in cytoplasmic stress granules in hypoxic cells, thus excluding them from cytoplasmic processing bodies. Thus our studies reveal a novel form of gene regulation in hypoxic cells, regulation of NMD via phosphorylation of eIF2α. This finding has potential significance in many disease states, but particularly in thalassemia, where many of the stresses which phosphorylate eIF2α occur, and where the stress response and regulation of mutated β globin mRNAs may be particularly important.
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Bartkowiak, Kai, Claudia Koch, Sebastian Gärtner, Antje Andreas, Tobias M. Gorges, and Klaus Pantel. "In Vitro Modeling of Reoxygenation Effects on mRNA and Protein Levels in Hypoxic Tumor Cells upon Entry into the Bloodstream." Cells 9, no. 5 (May 25, 2020): 1316. http://dx.doi.org/10.3390/cells9051316.
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Background: Solid epithelial tumors like breast cancer are the most frequent malignancy in women. Circulating tumor cells (CTCs) are frequently released from hypoxic areas into the blood, where CTCs face elevated oxygen concentrations. This reoxygenation might challenge the use of CTCs for liquid biopsy. Methods: We modeled this situation in vitro using the breast cancer cell lines—MCF-7, MDA-MB-468, MDA-MB-231—and the cell line BC-M1 established from DTCs in the bone marrow. Cells were cultured under hypoxia, followed by a reoxygenation pulse for 4 h, reflecting the circulation time of CTCs. Analyzed were gene products like EGFR, ErbB-2, EpCAM, PD-L1 on mRNA and protein level. Results: mRNAs of erbb2 or pdl1 and protein levels of PD-L1 displayed significant changes, whereas ErbB-2 protein levels remained constant. The strongest discrepancy between protein and mRNA levels under hypoxia was observed for EGFR, supporting the idea of cap-independent translation of egfr mRNA. Analyses of the phosphorylation of AKT, Erk 1/2, and Stat3 revealed strong alterations after reoxygenation. Conclusions: CTCs reaching secondary sites faster than reoxygenation could alter the mRNA and protein levels in the cells. CTC and DTC with high PD-L1 levels might become quiescent under hypoxia but were easily reactivated by reoxygenation.
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Katsakhyan, Levon, Sabina Swierczek, Andrew Artz, Elizabeth A. Price, Stanley L. Schrier, Harvey Jay Cohen, Josef T. Prchal, and Victor R. Gordeuk. "The Effect of IV Iron Therapy on HIF Pathway and HIF Regulated Genes in Elderly Patients with Unexplained Anemia." Blood 126, no. 23 (December 3, 2015): 4533. http://dx.doi.org/10.1182/blood.v126.23.4533.4533.
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Abstract LK, SS Equal contributions VG, JTP Equal credit as senior authors Prolyl hydroxylase 2 (encoded by EGLN1), the principle negative regulator of HIF-1 and HIF-2 (encoded by EPAS1), is an iron dependent enzyme (Kaelin WG et al. Mol Cell, 2008); thus iron deficiency can augment hypoxic responses (Zhang X et al Blood Cells Mol Dis, 2014). Because EPAS1 mRNA has a 5' iron regulatory element, iron deficiency may inhibit the translation of HIF-2α and downregulate its target genes (Sanchez M et al Nat Struct Mol Biol, 2007). The Partnership for Anemia: Clinical and Translational Trials in the Elderly conducted a trial to determine the efficacy of IV iron in patients with borderline iron deficiency (Price E et al. Blood Cells Mol Dis, 2014). We measured expression levels of HIF1A, EPAS1, EGLN1 and HIF target genes in platelets and granulocytes. Nineteen patients were treated with 200 mg IV iron sucrose weekly for 5 weeks. Blood was obtained at screening, one week after the second dose of IV iron and 8 weeks after completion of iron therapy. Granulocytes and platelets were isolated and their RNA reverse transcribed. Transcripts were quantified by real-time qT-PCR, and normalized to HPRT gene. The threshold cycle for the expression of each gene was calculated and compared to 5 healthy controls. We found a positive correlation between granulocyte and platelet mRNA of HIF1A, EPAS1 and EGLN1, and these relationships achieved a one-sided significance level of 0.1 or stronger for most data points for HIF1A and EPAS1 (Table 1). There was also a positive correlation for granulocyte and platelet mRNA of 5 of 7 hypoxia response genes (P of 0.1 or stronger in many comparisons; the strongest being for VEGF and PDK1). Table 1. Spearman correlation rho between granulocyte and platelet mRNAs (N = 17). Gene Screen TV2 FU2 Regulators of the hypoxic response HIF1A .52** .21 .40* EPAS1 .40* .54** .67** EGLN1 .28 .30 .09 Responders to the hypoxic response GLUT1 .44** .00 .07 HK1 .25 .20 .36* PDK1 .24 .55** .41* VEGF .68** .33* .62** FOXO3 -.10 .22 .45** BNIP3 .03 -.19 -.08 BNIP3L .15 -.05 .20 *one-sided P <0.10; **P <0.05 There were positive relationships in the expression of the three hypoxic response regulating genes with lower iron stores, as reflected in three measures, and these tended to be strongest for the TfR to log ferritin index (Table 2). These relationships also tended to hold for HK1, PDK1, VEGF and BNIP3L in both types of cells, but the relationships were stronger in platelets. Table 2. Spearman correlation for relationship between iron status and gene expression at screening. A negative correlation with ferritin and positive correlation with TfR and TfR/log ftn indicates increased gene expression with lower iron stores. Granulocytes Platelets Ferritin TfR TfR/log ftn Ferritin TfR TfR/log ftn Regulators of the hypoxic response HIF1A -.04 .05 .15 -.26 .41* .52** EPAS1 -.31 .090 .23 -.016 .15 .09 EGLN1 -.18 .26 .31 -.33* .57** .66** Responders to the hypoxic response GLUT1 .39* -.33 -.38* .27 .35* .23 HK1 -.20 .016 .07 -.22 .23 .23 PDK1 -.22 .31 .39* -.38* .16 .24 VEGF -.22 .12 .30 -.22 .48** .52** FOXO3 .10 -.097 -.061] -.19 -.15 -.14 BNIP3 -.04 -.10 -.007 -.18 -.30 -.25 BNIP3L -.08 .13 .21 -.36* .43** .50** Trends for change in gene expression with iron therapy were also observed. Iron therapy led to decreased expression of HIF1A and EGLN1 in both cell types but increased expression of EPAS1; these relationships were stronger in granulocytes, where they achieved a one-sided significance of P <0.2. IV iron tended to be associated with reduced expression of a panel of 7 HIF target genes, more so in granulocytes than in platelets. Expression of FOXO3 did not decrease with IV iron, perhaps consistent with its being a target of HIF-2 as well as HIF-1. Expression of hypoxic response regulating genes tended to correlate between platelets and granulocytes, as did expression of one-half of hypoxic response genes tested. Furthermore, expected relationships with iron status were observed for the expression of HIF1A, EPAS1 and EGLIN1. However, variable responses were found in the expression of certain HIF target genes in response to iron therapy that may be related to a balance of decreased HIF-a protein with enhanced translation of HIF-2a. Transcripts of these HIF regulated and HIF pathway genes are being compared to normals and to non-anemic elderly subjects to determine if anemia in the elderly is associated with a blunted hypoxic response. Disclosures No relevant conflicts of interest to declare.