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      The p38α Stress Kinase Suppresses Aneuploidy Tolerance by Inhibiting Hif-1α

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          Deviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically, however, karyotype heterogeneity drives tumor evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate glycolysis and avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones. We also show that p38 deficiency upregulates the hypoxia-inducible transcription factor Hif-1α and that inhibiting Hif-1α restores apoptosis in p38-deficent cells. Because hypoxia and aneuploidy are both barriers to tumor progression, the ability of Hif-1α to promote cell survival following chromosome missegregation raises the possibility that aneuploidy tolerance coevolves with adaptation to hypoxia.

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          Highlights

          • The p38 stress response kinase promotes apoptosis following aneuploidy induction

          • Aneuploidy-induced metabolic collapse is ameliorated upon inhibition of p38

          • p38 deficiency upregulates Hif-1α, buffering aneuploidy-induced metabolic collapse

          • Aneuploidy tolerance may have coevolved with adaptation to hypoxia

          Abstract

          Simões-Sousa et al. show that chromosome missegregation induces metabolic collapse and apoptosis, mediated by the p38 stress response kinase. Inhibiting p38 elevates Hif-1α, boosts glycolysis, and limits metabolic collapse, in turn allowing expansion of aneuploid clones. Adapting to hypoxia during tumor development may therefore also permit aneuploidy tolerance.

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          Most cited references52

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          p38 MAP-kinases pathway regulation, function and role in human diseases.

          Mammalian p38 mitogen-activated protein kinases (MAPKs) are activated by a wide range of cellular stresses as well as in response to inflammatory cytokines. There are four members of the p38MAPK family (p38alpha, p38beta, p38gamma and p38delta) which are about 60% identical in their amino acid sequence but differ in their expression patterns, substrate specificities and sensitivities to chemical inhibitors such as SB203580. A large body of evidences indicates that p38MAPK activity is critical for normal immune and inflammatory response. The p38MAPK pathway is a key regulator of pro-inflammatory cytokines biosynthesis at the transcriptional and translational levels, which makes different components of this pathway potential targets for the treatment of autoimmune and inflammatory diseases. However, recent studies have shed light on the broad effect of p38MAPK activation in the control of many other aspects of the physiology of the cell, such as control of cell cycle or cytoskeleton remodelling. Here we focus on these emergent roles of p38MAPKs and their implication in different pathologies.
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            Effects of aneuploidy on cellular physiology and cell division in haploid yeast.

            Aneuploidy is a condition frequently found in tumor cells, but its effect on cellular physiology is not known. We have characterized one aspect of aneuploidy: the gain of extra chromosomes. We created a collection of haploid yeast strains that each bear an extra copy of one or more of almost all of the yeast chromosomes. Their characterization revealed that aneuploid strains share a number of phenotypes, including defects in cell cycle progression, increased glucose uptake, and increased sensitivity to conditions interfering with protein synthesis and protein folding. These phenotypes were observed only in strains carrying additional yeast genes, which indicates that they reflect the consequences of additional protein production as well as the resulting imbalances in cellular protein composition. We conclude that aneuploidy causes not only a proliferative disadvantage but also a set of phenotypes that is independent of the identity of the individual extra chromosomes.
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              Cancer's molecular sweet tooth and the Warburg effect.

              More than 80 years ago, the renowned biochemist Otto Warburg described how cancer cells avidly consume glucose and produce lactic acid under aerobic conditions. Recent studies arguing that cancer cells benefit from this phenomenon, termed the Warburg effect, have renewed discussions about its exact role as cause, correlate, or facilitator of cancer. Molecular advances in this area may reveal tactics to exploit the cancer cell's "sweet tooth" for cancer therapy.
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                Author and article information

                Contributors
                Journal
                Cell Rep
                Cell Rep
                Cell Reports
                Cell Press
                2211-1247
                16 October 2018
                16 October 2018
                16 October 2018
                : 25
                : 3
                : 749-760.e6
                Affiliations
                [1 ]Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, Wilmslow Road, Manchester M20 4QL, UK
                [2 ]European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands
                [3 ]Wellcome Centre Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
                Author notes
                []Corresponding author stephen.taylor@ 123456manchester.ac.uk
                [4]

                Lead Contact

                Article
                S2211-1247(18)31505-5
                10.1016/j.celrep.2018.09.060
                6205844
                30332653
                af9ce997-cb01-4b68-a8d5-a3f09e0c5bf3
                © 2018 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 13 March 2018
                : 25 June 2018
                : 18 September 2018
                Categories
                Article

                Cell biology
                mitosis,chromosome instability,aneuploidy
                Cell biology
                mitosis, chromosome instability, aneuploidy

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