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Gregg L. Semenza

Bio: Gregg L. Semenza is a academic researcher from Johns Hopkins University School of Medicine. The author has contributed to research in topic(s): Hypoxia (medical) & Transcription factor. The author has an hindex of 168, co-authored 502 publication(s) receiving 130316 citation(s). Previous affiliations of Gregg L. Semenza include Max Delbrück Center for Molecular Medicine & University of Maryland, Baltimore.

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Papers
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Journal ArticleDOI: 10.1038/NRC1187
Gregg L. Semenza1Institutions (1)
Abstract: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

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Topics: HIF1A (60%), Hypoxia-inducible factors (56%), Angiogenesis (52%) ...read more

5,551 Citations


Open accessJournal ArticleDOI: 10.1073/PNAS.92.12.5510
Abstract: Hypoxia-inducible factor 1 (HIF-1) is found in mammalian cells cultured under reduced O2 tension and is necessary for transcriptional activation mediated by the erythropoietin gene enhancer in hypoxic cells. We show that both HIF-1 subunits are basic-helix-loop-helix proteins containing a PAS domain, defined by its presence in the Drosophila Per and Sim proteins and in the mammalian ARNT and AHR proteins. HIF-1 alpha is most closely related to Sim. HIF-1 beta is a series of ARNT gene products, which can thus heterodimerize with either HIF-1 alpha or AHR. HIF-1 alpha and HIF-1 beta (ARNT) RNA and protein levels were induced in cells exposed to 1% O2 and decayed rapidly upon return of the cells to 20% O2, consistent with the role of HIF-1 as a mediator of transcriptional responses to hypoxia.

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5,366 Citations


Journal ArticleDOI: 10.1080/15548627.2015.1100356
Daniel J. Klionsky1, Kotb Abdelmohsen2, Akihisa Abe3, Joynal Abedin4  +2519 moreInstitutions (695)
21 Jan 2016-Autophagy
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

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Topics: MAP1LC3B (64%), Chaperone-mediated autophagy (62%), BECN1 (62%) ...read more

4,756 Citations


Open accessJournal ArticleDOI: 10.1128/MCB.16.9.4604
Jo A. Forsythe1, Bing-Hua Jiang1, Narayan V. Iyer1, Faton Agani1  +3 moreInstitutions (1)
Abstract: Expression of vascular endothelial growth factor (VEGF) is induced in cells exposed to hypoxia or ischemia. Neovascularization stimulated by VEGF occurs in several important clinical contexts, including myocardial ischemia, retinal disease, and tumor growth. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic helix-loop-helix protein that activates transcription of the human erythropoietin gene in hypoxic cells. Here we demonstrate the involvement of HIF-1 in the activation of VEGF transcription. VEGF 5'-flanking sequences mediated transcriptional activation of reporter gene expression in hypoxic Hep3B cells. A 47-bp sequence located 985 to 939 bp 5' to the VEGF transcription initiation site mediated hypoxia-inducible reporter gene expression directed by a simian virus 40 promoter element that was otherwise minimally responsive to hypoxia. When reporters containing VEGF sequences, in the context of the native VEGF or heterologous simian virus 40 promoter, were cotransfected with expression vectors encoding HIF-1alpha and HIF-1beta (ARNT [aryl hydrocarbon receptor nuclear translocator]), reporter gene transcription was much greater in both hypoxic and nonhypoxic cells than in cells transfected with the reporter alone. A HIF-1 binding site was demonstrated in the 47-bp hypoxia response element, and a 3-bp substitution eliminated the ability of the element to bind HIF-1 and to activate transcription in response to hypoxia and/or recombinant HIF-1. Cotransfection of cells with an expression vector encoding a dominant negative form of HIF-1alpha inhibited the activation of reporter transcription in hypoxic cells in a dose-dependent manner. VEGF mRNA was not induced by hypoxia in mutant cells that do not express the HIF-1beta (ARNT) subunit. These findings implicate HIF-1 in the activation of VEGF transcription in hypoxic cells.

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3,523 Citations


Open accessJournal ArticleDOI: 10.1016/J.CMET.2006.02.002
01 Mar 2006-Cell Metabolism
Abstract: Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1alpha null cells increases ATP levels, attenuates hypoxic ROS generation, and rescues these cells from hypoxia-induced apoptosis. These studies reveal a hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production.

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2,811 Citations


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Open accessJournal ArticleDOI: 10.1016/J.CELL.2011.02.013
Douglas Hanahan1, Robert A. Weinberg2Institutions (2)
04 Mar 2011-Cell
Abstract: The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.

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42,275 Citations


Open access
28 Jul 2005-
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1(PfPMP1)与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员,通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

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18,940 Citations


Journal ArticleDOI: 10.1016/J.BIOCEL.2006.07.001
Abstract: Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NAD(P)H) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents, in the function of a number of cellular signalling pathways, and the induction of a mitogenic response. Ironically, various ROS-mediated actions in fact protect cells against ROS-induced oxidative stress and re-establish or maintain "redox balance" termed also "redox homeostasis". The "two-faced" character of ROS is clearly substantiated. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. This review will describe the: (i) chemistry and biochemistry of ROS/RNS and sources of free radical generation; (ii) damage to DNA, to proteins, and to lipids by free radicals; (iii) role of antioxidants (e.g. glutathione) in the maintenance of cellular "redox homeostasis"; (iv) overview of ROS-induced signaling pathways; (v) role of ROS in redox regulation of normal physiological functions, as well as (vi) role of ROS in pathophysiological implications of altered redox regulation (human diseases and ageing). Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing. Topics of current debate are also reviewed such as the question whether excessive formation of free radicals is a primary cause or a downstream consequence of tissue injury.

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Topics: Free-radical theory of aging (61%), Oxidative stress (60%), Reactive nitrogen species (55%) ...read more

10,980 Citations


Open accessJournal ArticleDOI: 10.1152/PHYSREV.00018.2001
Abstract: At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

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  • FIG. 3. Regulatory events and their dysregulation depend on the magnitude and duration of the change in ROS or reactive nitrogen species (RNS) concentration. ROS and RNS normally occur in living tissues at relatively low steady-state levels. The regulated increase in superoxide or nitric oxide production leads to a temporary imbalance that forms the basis of redox regulation. The persistent production of abnormally large amounts of ROS or RNS, however, may lead to persistent changes in signal transduction and gene expression, which, in turn, may give rise to pathological conditions.
    FIG. 3. Regulatory events and their dysregulation depend on the magnitude and duration of the change in ROS or reactive nitrogen species (RNS) concentration. ROS and RNS normally occur in living tissues at relatively low steady-state levels. The regulated increase in superoxide or nitric oxide production leads to a temporary imbalance that forms the basis of redox regulation. The persistent production of abnormally large amounts of ROS or RNS, however, may lead to persistent changes in signal transduction and gene expression, which, in turn, may give rise to pathological conditions.
  • FIG. 12. Effect of substrate availability on ROS production. Substantial amounts of superoxide are produced at the semiubiquinone component of the mitochondrial electron transport chain. The probability of ROS production is increased if the influx of electrons is high and the consumption of electrons by cytochrome oxidase in the mitochondrial complex IV relatively low. Consumption of electrons is typically low if the proton gradient is high, i.e., if only a few protons are being consumed by the ATP-generating system as a result of relatively high ATP and low ADP concentrations. This condition normally inhibits the glycolytic pathway and the influx of further energy substrates into the mitochondria. At high glucose concentrations, e.g., as a result of inadequate glycogen synthase (GS) activity, this control may be overridden, resulting in increased ROS production. PFK, phosphofructokinase.
    FIG. 12. Effect of substrate availability on ROS production. Substantial amounts of superoxide are produced at the semiubiquinone component of the mitochondrial electron transport chain. The probability of ROS production is increased if the influx of electrons is high and the consumption of electrons by cytochrome oxidase in the mitochondrial complex IV relatively low. Consumption of electrons is typically low if the proton gradient is high, i.e., if only a few protons are being consumed by the ATP-generating system as a result of relatively high ATP and low ADP concentrations. This condition normally inhibits the glycolytic pathway and the influx of further energy substrates into the mitochondria. At high glucose concentrations, e.g., as a result of inadequate glycogen synthase (GS) activity, this control may be overridden, resulting in increased ROS production. PFK, phosphofructokinase.
  • FIG. 4. Schematic model of OxyR activation. The regulatory protein OxyR is activated by the formation of disulfide bridges. This process is mediated either by hydrogen peroxide (H2O2) or by oxidative changes in the intracellular thiol/disulfide redox state.
    FIG. 4. Schematic model of OxyR activation. The regulatory protein OxyR is activated by the formation of disulfide bridges. This process is mediated either by hydrogen peroxide (H2O2) or by oxidative changes in the intracellular thiol/disulfide redox state.
  • FIG. 11. Distinct redox requirements in the induction and execution of signal cascades: hypothetical model. The antigen-responsive signaling cascades of lyphocytes are strongly enhanced by the ROS produced in large quantities by macrophages in the inflammatory environment. Glycolytically active macrophages produce also large amounts of lactate, which, in turn, induces a decrease in the intracellular glutathione level of the lymphocyte. Experiments with Molt-4 cells have shown that the 4-O-tetradecanoylphorbol 13-acetate (TPA)-induced activation of activator protein 1 (AP-1) and nuclear factor kB (NF-kB) DNA-binding activity is inhibited if the cells are subjected to reducing conditions (1 mM dithiothreitol) before TPA treatment but strongly enhanced if the cells are subjected to reducing conditions 1 h after TPA stimulation. Moreover, the proliferative response and the induction of many types of immunological responses are strongly dependent on relatively high intracellular glutathione levels. The delivery of reduced cysteine by certain types of macrophages to the lymphocytes has been shown to play an important role in the maintenance of adequate glutathione levels in lymphocytes.
    FIG. 11. Distinct redox requirements in the induction and execution of signal cascades: hypothetical model. The antigen-responsive signaling cascades of lyphocytes are strongly enhanced by the ROS produced in large quantities by macrophages in the inflammatory environment. Glycolytically active macrophages produce also large amounts of lactate, which, in turn, induces a decrease in the intracellular glutathione level of the lymphocyte. Experiments with Molt-4 cells have shown that the 4-O-tetradecanoylphorbol 13-acetate (TPA)-induced activation of activator protein 1 (AP-1) and nuclear factor kB (NF-kB) DNA-binding activity is inhibited if the cells are subjected to reducing conditions (1 mM dithiothreitol) before TPA treatment but strongly enhanced if the cells are subjected to reducing conditions 1 h after TPA stimulation. Moreover, the proliferative response and the induction of many types of immunological responses are strongly dependent on relatively high intracellular glutathione levels. The delivery of reduced cysteine by certain types of macrophages to the lymphocytes has been shown to play an important role in the maintenance of adequate glutathione levels in lymphocytes.
  • FIG. 7. Functions of ROS in the immunological response against environmental pathogens. The massive production of ROS (oxidative burst) by activated macrophages in the inflammatory environment provides a first line of defense against environmental pathogens. A certain fraction of pathogens, however, may escape this rapid but moderately effective manifestation of “innate immunity” and may generate within a few days a large progeny of pathogens. Antigenic peptides generated within the activated macrophages by the breakdown of pathogens are presented by major histocompatibility complex (MHC) determinants to the antigen receptors (AR) of T lymphocytes. This interaction triggers the proliferation and differentiation of the T cells and leads within a few days to a large progeny of immunological effector cells. The effector cells provide a highly effective and antigen-specific immunological defense. ROS that are concomitantly produced by the activated macrophages in the inflammatory environment enhance the AR-mediated signal cascades and decrease thereby the activation threshold of the T cells. Without this effect, the T lymphocytes would require relatively large concentrations of antigenic peptides and would lose valuable time in their “race” with the proliferating pathogens. In this situation time may be a matter of life or death for the organism.
    FIG. 7. Functions of ROS in the immunological response against environmental pathogens. The massive production of ROS (oxidative burst) by activated macrophages in the inflammatory environment provides a first line of defense against environmental pathogens. A certain fraction of pathogens, however, may escape this rapid but moderately effective manifestation of “innate immunity” and may generate within a few days a large progeny of pathogens. Antigenic peptides generated within the activated macrophages by the breakdown of pathogens are presented by major histocompatibility complex (MHC) determinants to the antigen receptors (AR) of T lymphocytes. This interaction triggers the proliferation and differentiation of the T cells and leads within a few days to a large progeny of immunological effector cells. The effector cells provide a highly effective and antigen-specific immunological defense. ROS that are concomitantly produced by the activated macrophages in the inflammatory environment enhance the AR-mediated signal cascades and decrease thereby the activation threshold of the T cells. Without this effect, the T lymphocytes would require relatively large concentrations of antigenic peptides and would lose valuable time in their “race” with the proliferating pathogens. In this situation time may be a matter of life or death for the organism.
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8,461 Citations


Journal ArticleDOI: 10.1038/NM0603-669
01 Jun 2003-Nature Medicine
Abstract: Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions. The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2, which differ considerably in signaling properties. Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies. VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration.

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8,400 Citations


Performance
Metrics

Author's H-index: 168

No. of papers from the Author in previous years
YearPapers
20219
20207
20197
201810
201716
201623

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Author's top 5 most impactful journals

Journal of Biological Chemistry

29 papers, 13.9K citations

Cancer Research

22 papers, 7.9K citations

Journal of Molecular Medicine

19 papers, 522 citations

Journal of Clinical Investigation

15 papers, 2.7K citations

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