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      Drugging in the absence of p53

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          Abstract

          Inactivation of the p53 gene is a key driver of tumorigenesis in various cancer cohorts and types. The quest for a successful p53-based therapy that holds the promise of treating more than half of the cancer population has culminated in extensive knowledge about the role and function of p53 and led to new proposed innovative strategies against p53-defective cancers. We will discuss some of these latest studies with a focus on metabolic regulation and DNA damage response and also highlight novel functions of p53 in these pathways that may provide a contemporary rationale for targeting p53 loss in tumors.

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          TIGAR, a p53-Inducible Regulator of Glycolysis and Apoptosis

          Karim Bensaad, Atsushi Tsuruta, Mary A. Selak … (2006)
          The p53 tumor-suppressor protein prevents cancer development through various mechanisms, including the induction of cell-cycle arrest, apoptosis, and the maintenance of genome stability. We have identified a p53-inducible gene named TIGAR (TP53-induced glycolysis and apoptosis regulator). TIGAR expression lowered fructose-2,6-bisphosphate levels in cells, resulting in an inhibition of glycolysis and an overall decrease in intracellular reactive oxygen species (ROS) levels. These functions of TIGAR correlated with an ability to protect cells from ROS-associated apoptosis, and consequently, knockdown of endogenous TIGAR expression sensitized cells to p53-induced death. Expression of TIGAR may therefore modulate the apoptotic response to p53, allowing survival in the face of mild or transient stress signals that may be reversed or repaired. The decrease of intracellular ROS levels in response to TIGAR may also play a role in the ability of p53 to protect from the accumulation of genomic damage.
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            AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.

            Russell G. Jones, David Plas, Sara Kubek … (2005)
            Replicative cell division is an energetically demanding process that can be executed only if cells have sufficient metabolic resources to support a doubling of cell mass. Here we show that proliferating mammalian cells have a cell-cycle checkpoint that responds to glucose availability. The glucose-dependent checkpoint occurs at the G(1)/S boundary and is regulated by AMP-activated protein kinase (AMPK). This cell-cycle arrest occurs despite continued amino acid availability and active mTOR. AMPK activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate AMPK-dependent cell-cycle arrest. AMPK-induced p53 activation promotes cellular survival in response to glucose deprivation, and cells that have undergone a p53-dependent metabolic arrest can rapidly reenter the cell cycle upon glucose restoration. However, persistent activation of AMPK leads to accelerated p53-dependent cellular senescence. Thus, AMPK is a cell-intrinsic regulator of the cell cycle that coordinates cellular proliferation with carbon source availability.
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              Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence.

              Tongyuan Li, Ning Kon, Le Jiang … (2012)
              Cell-cycle arrest, apoptosis, and senescence are widely accepted as the major mechanisms by which p53 inhibits tumor formation. Nevertheless, it remains unclear whether they are the rate-limiting steps in tumor suppression. Here, we have generated mice bearing lysine to arginine mutations at one (p53(K117R)) or three (p53(3KR); K117R+K161R+K162R) of p53 acetylation sites. Although p53(K117R/K117R) cells are competent for p53-mediated cell-cycle arrest and senescence, but not apoptosis, all three of these processes are ablated in p53(3KR/3KR) cells. Surprisingly, unlike p53 null mice, which rapidly succumb to spontaneous thymic lymphomas, early-onset tumor formation does not occur in either p53(K117R/K117R) or p53(3KR/3KR) animals. Notably, p53(3KR) retains the ability to regulate energy metabolism and reactive oxygen species production. These findings underscore the crucial role of acetylation in differentially modulating p53 responses and suggest that unconventional activities of p53, such as metabolic regulation and antioxidant function, are critical for suppression of early-onset spontaneous tumorigenesis. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Chandra S Verma: Role: Editor
                Journal
                Journal ID (nlm-ta): J Mol Cell Biol
                Journal ID (iso-abbrev): J Mol Cell Biol
                Journal ID (publisher-id): jmcb
                Title: Journal of Molecular Cell Biology
                Publisher: Oxford University Press
                ISSN (Print): 1674-2788
                ISSN (Electronic): 1759-4685
                Publication date Collection: March 2019
                Publication date (Electronic): 28 March 2019
                Publication date PMC-release: 28 March 2019
                Volume: 11
                Issue: 3 , Special Issue: p53: Updates on Mechanisms, Bology and Therapy (I)
                Pages: 255-264
                Affiliations
                [1 ]Institute of Molecular and Cell Biology, A*STAR, Singapore
                [2 ]Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
                [3 ]Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
                Author notes
                Correspondence to: Chit Fang Cheok, E-mail: cheokcf@ 123456imcb.a-star.edu.sg
                Author information
                http://orcid.org/0000-0001-8242-3995
                Article
                Publisher ID: mjz012
                DOI: 10.1093/jmcb/mjz012
                PMC ID: 6478123
                PubMed ID: 30865230
                SO-VID: 8f1a3dfb-4516-44b7-80a0-3e0af3552b7f
                Copyright © © The Author(s) (2019). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                History
                Date received : 25 October 2018
                Date revision received : 29 December 2018
                Date accepted : 04 January 2019
                Page count
                Pages: 10
                Funding
                Funded by: Institute of Molecular and Cell Biology (IMCB) 10.13039/501100007674
                Funded by: Agency of Science, Technology and Research (A*STAR), Singapore
                Categories
                Subject: Invited Review

                Keywords: therapeutics,metabolism,dna damage,replication stress,p53,synthetic lethality
                Data availability:
                Keywords: therapeutics, metabolism, dna damage, replication stress, p53, synthetic lethality

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