Pyruvate Kinase M2 Is a PHD3-Stimulated Coactivator for Hypoxia-Inducible Factor 1
TL;DR: In this article, the pyruvate kinase isoforms PKM1 and PKM2 are alternatively spliced products of the PKM 2 gene, and they are activated by hypoxia-inducible factor 1 (HIF-1).
About: This article is published in Cell.The article was published on 2011-05-27 and is currently open access. It has received 1167 citations till now. The article focuses on the topics: Coactivator & PKM2.
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TL;DR: It is argued that altered metabolism has attained the status of a core hallmark of cancer.
2,623 citations
Cites background from "Pyruvate Kinase M2 Is a PHD3-Stimul..."
...Cells Is to Facilitate Anabolic Metabolism Accompanying the resurgence of interest in the metabolic effects of PKM2 have been recent reports on ‘‘non-metabolic’’ functions of PKM2 (Luo et al., 2011; Yang et al., 2011)....
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TL;DR: Oxygen homeostasis represents an organizing principle for understanding metazoan evolution, development, physiology, and pathobiology and rapid progress is being made in elucidating homeostatic roles of HIFs in many physiological systems, determining pathological consequences of H IF dysregulation in chronic diseases, and investigating potential targeting of Hifs for therapeutic purposes.
2,450 citations
Cites background from "Pyruvate Kinase M2 Is a PHD3-Stimul..."
...…transition (Mak et al., 2010), genetic instability (Huang et al., 2007), vascularization (Liao and Johnson, 2007), glucose metab- olism (Luo et al., 2011), pH regulation (Swietach et al., 2007), immune evasion (Lukashev et al., 2007), invasion andmetastasis (Chan andGiaccia, 2007),…...
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TL;DR: A brief refresher course on six of the major metabolic pathways involved in immunometabolism is provided, giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response.
Abstract: Immunometabolism is emerging an important area of immunological research, but for many immunologists the complexity of the field can be daunting. Here, the authors provide an overview of six key metabolic pathways that occur in immune cells and explain what is known (and what is still to be uncovered) concerning their effects on immune cell function. In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.
1,857 citations
TL;DR: Cancer cells then reprogramme adjacent stromal cells to optimize the cancer cell environment and activate out-of-context programmes that are important in development, stress response, wound healing and nutritional status.
Abstract: Contrary to conventional wisdom, functional mitochondria are essential for the cancer cell. Although mutations in mitochondrial genes are common in cancer cells, they do not inactivate mitochondrial energy metabolism but rather alter the mitochondrial bioenergetic and biosynthetic state. These states communicate with the nucleus through mitochondrial 'retrograde signalling' to modulate signal transduction pathways, transcriptional circuits and chromatin structure to meet the perceived mitochondrial and nuclear requirements of the cancer cell. Cancer cells then reprogramme adjacent stromal cells to optimize the cancer cell environment. These alterations activate out-of-context programmes that are important in development, stress response, wound healing and nutritional status.
1,709 citations
TL;DR: Clinical trials can (and should) be initiated to test the hypothesis that incorporation of HIF inhibitors into current standard-of-care therapy will increase the survival of cancer patients.
1,281 citations
References
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TL;DR: 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.
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.
6,024 citations
"Pyruvate Kinase M2 Is a PHD3-Stimul..." refers background in this paper
...Intratumoral hypoxia is commonly found in aggressive solid cancers, leading toHIF-1aaccumulation (Harris, 2002;Semenza, 2003)....
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TL;DR: 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.
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.
5,729 citations
"Pyruvate Kinase M2 Is a PHD3-Stimul..." refers background in this paper
...HIF-1 is a transcription factor that consists of an O2-regulated HIF-1a subunit and a constitutively expressed HIF-1b subunit (Wang et al., 1995)....
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TL;DR: Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death, and many elements of the hypoxia-response pathway are good candidates for therapeutic targeting.
Abstract: Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death. Cancer cells have adapted these pathways, allowing tumours to survive and even grow under hypoxic conditions, and tumour hypoxia is associated with poor prognosis and resistance to radiation therapy. Many elements of the hypoxia-response pathway are therefore good candidates for therapeutic targeting.
4,847 citations
"Pyruvate Kinase M2 Is a PHD3-Stimul..." refers background in this paper
...Intratumoral hypoxia is commonly found in aggressive solid cancers, leading toHIF-1aaccumulation (Harris, 2002;Semenza, 2003)....
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...Activation of hypoxia-inducible factor 1 (HIF-1), which commonly occurs in human cancers either as a result of hypoxia or genetic alterations (Harris, 2002; Semenza, 2010), leads to a switch from oxidative to glycolytic metabolism (Seagroves et al....
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...Activation of hypoxia-inducible factor 1 (HIF-1), which commonly occurs in human cancers either as a result of hypoxia or genetic alterations (Harris, 2002; Semenza, 2010), leads to a switch from oxidative to glycolytic metabolism (Seagroves et al., 2001;Wheaton andChandel, 2011)....
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...HIF-1 activates transcription of genes encoding proteins that are involved in key aspects of cancer biology, including angiogenesis, metabolism, cell survival, invasion, and metastasis (Harris, 2002; Melillo, 2007; Semenza, 2010)....
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TL;DR: In this article, the authors propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions, which leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity.
Abstract: If carcinogenesis occurs by somatic evolution, then common components of the cancer phenotype result from active selection and must, therefore, confer a significant growth advantage. A near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging. We propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity. Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion.
4,361 citations
TL;DR: Direct modulation of recombinant enzyme activity by graded hypoxia, iron chelation, and cobaltous ions mirrors the characteristics of HIF induction in vivo, fulfilling requirements for these enzymes being oxygen sensors that regulate HIF.
3,188 citations