14
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      PKM2 Interacts With the Cdk1-CyclinB Complex to Facilitate Cell Cycle Progression in Gliomas

      research-article

      Read this article at

      Bookmark
          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.

          Abstract

          PKM2 is a phosphotyrosine-binding glycolytic enzyme upregulated in many cancers, including glioma, and contributes to tumor growth by regulating cell cycle progression. We noted, however, that in multiple glioma cell lines, PKM2 knock-down resulted in an accumulation of cells in G2-M phase. Moreover, PKM2 knock-down decreased Cdk1 activity while introducing a constitutively active Cdk1 reversed the effects of PKM2 knock-down on cell cycle progression. The means by which PKM2 increases Cdk1 activity have not been described. Transient interaction of T14/Y15-phosphorylated Cdk1 with cyclin B allows Cdk7-mediated pT161 Cdk1 phosphorylation followed by cdc25C-mediated removal of pT14/Y15 and activation of Cdk1 in cycling cells. In the present course of investigation, PKM2 modulation did not influence Cdk7 activity, but phosphotyrosine binding forms of PKM2 co-immunoprecipitated with pY15-containing Cdk1-cyclinB and enhanced formation of active pT161 Cdk1-cyclin B complexes. Moreover, exogenous expression of phosphotyrosine binding forms of PKM2 reversed the effects of PKM2 knock-down on G2-M arrest. We here show that PKM2 binds and stabilize otherwise transient pY15-containing Cdk1-cyclinB complexes that in turn facilitate Cdk1-cyclin B activation and entry of cells into mitosis. These results, therefore, establish metabolic enzyme PKM2 as a direct interactor and activator of Cdk1-cyclin B complex and thereby directly controls mitotic progression and the growth of brain tumor cells.

          Related collections

          Most cited references34

          • Record: found
          • Abstract: found
          • Article: not found

          Cdk1 is sufficient to drive the mammalian cell cycle.

          Unicellular organisms such as yeasts require a single cyclin-dependent kinase, Cdk1, to drive cell division. In contrast, mammalian cells are thought to require the sequential activation of at least four different cyclin-dependent kinases, Cdk2, Cdk3, Cdk4 and Cdk6, to drive cells through interphase, as well as Cdk1 to proceed through mitosis. This model has been challenged by recent genetic evidence that mice survive in the absence of individual interphase Cdks. Moreover, most mouse cell types proliferate in the absence of two or even three interphase Cdks. Similar results have been obtained on ablation of some of the activating subunits of Cdks, such as the D-type and E-type cyclins. Here we show that mouse embryos lacking all interphase Cdks (Cdk2, Cdk3, Cdk4 and Cdk6) undergo organogenesis and develop to midgestation. In these embryos, Cdk1 binds to all cyclins, resulting in the phosphorylation of the retinoblastoma protein pRb and the expression of genes that are regulated by E2F transcription factors. Mouse embryonic fibroblasts derived from these embryos proliferate in vitro, albeit with an extended cell cycle due to inefficient inactivation of Rb proteins. However, they become immortal on continuous passage. We also report that embryos fail to develop to the morula and blastocyst stages in the absence of Cdk1. These results indicate that Cdk1 is the only essential cell cycle Cdk. Moreover, they show that in the absence of interphase Cdks, Cdk1 can execute all the events that are required to drive cell division.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Cyclin-dependent kinases: engines, clocks, and microprocessors.

            D Morgan (1997)
            Cyclin-dependent kinases (Cdks) play a well-established role in the regulation of the eukaryotic cell division cycle and have also been implicated in the control of gene transcription and other processes. Cdk activity is governed by a complex network of regulatory subunits and phosphorylation events whose precise effects on Cdk conformation have been revealed by recent crystallographic studies. In the cell, these regulatory mechanisms generate an interlinked series of Cdk oscillators that trigger the events of cell division.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found

              The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth.

              Many tumour cells have elevated rates of glucose uptake but reduced rates of oxidative phosphorylation. This persistence of high lactate production by tumours in the presence of oxygen, known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago. How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is necessary for the shift in cellular metabolism to aerobic glycolysis and that this promotes tumorigenesis. Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase. Here we use short hairpin RNA to knockdown pyruvate kinase M2 expression in human cancer cell lines and replace it with pyruvate kinase M1. Switching pyruvate kinase expression to the M1 (adult) isoform leads to reversal of the Warburg effect, as judged by reduced lactate production and increased oxygen consumption, and this correlates with a reduced ability to form tumours in nude mouse xenografts. These results demonstrate that M2 expression is necessary for aerobic glycolysis and that this metabolic phenotype provides a selective growth advantage for tumour cells in vivo.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                22 March 2022
                2022
                : 12
                : 844861
                Affiliations
                [1] 1 Department of Neurological Surgery, University of California, San Francisco , San Francisco, CA, United States
                [2] 2 Department of Neurosurgery, Fujita Health University , Toyoake, Japan
                [3] 3 Department of Neurosurgery, Xiangya Hospital, Central South University , Changsha, China
                [4] 4 The Kristian Gerhard Jebsen Brain Tumor Research Centre, Department of Biomedicine, University of Bergen , Bergen, Norway
                Author notes

                Edited by: Justin Lathia, Case Western Reserve University, United States

                Reviewed by: Sonikpreet Aulakh, West Virginia University, United States; Jason M. Miska, Northwestern University, United States; Loic P. Deleyrolle, University of Florida, United States

                *Correspondence: Joydeep Mukherjee, joydeep.mukherjee@ 123456ucsf.edu

                †These authors have contributed equally to this work

                This article was submitted to Neuro-Oncology and Neurosurgical Oncology, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2022.844861
                8981990
                35392228
                53e2dfce-a72c-4c57-b012-149dbcfa6006
                Copyright © 2022 Ohba, Tang, Johannessen and Mukherjee

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 December 2021
                : 24 February 2022
                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 34, Pages: 12, Words: 5556
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                pkm2,g2-m arrest,cdk1,cyclin b,glioma
                Oncology & Radiotherapy
                pkm2, g2-m arrest, cdk1, cyclin b, glioma

                Comments

                Comment on this article