Dying to Survive—The p53 Paradox

Abstract

The p53 tumour suppressor is best known for its canonical role as “guardian of the genome”, activating cell cycle arrest and DNA repair in response to DNA damage which, if irreparable or sustained, triggers activation of cell death. However, despite an enormous amount of work identifying the breadth of the gene regulatory networks activated directly and indirectly in response to p53 activation, how p53 activation results in different cell fates in response to different stress signals in homeostasis and in response to p53 activating anti-cancer treatments remains relatively poorly understood. This is likely due to the complex interaction between cell death mechanisms in which p53 has been activated, their neighbouring stressed or unstressed cells and the local stromal and immune microenvironment in which they reside. In this review, we evaluate our understanding of the burgeoning number of cell death pathways affected by p53 activation and how these may paradoxically suppress cell death to ensure tissue integrity and organismal survival. We also discuss how these functions may be advantageous to tumours that maintain wild-type p53, the understanding of which may provide novel opportunity to enhance treatment efficacy.

Parthenolide and Its Soluble Analogues: Multitasking Compounds with Antitumor Properties

“…One example is given by the effect of PN on the tumor suppressor/proapoptotic transcription factor p53. It is well known that p53 is key regulator in a molecular network establishing the cell fate due to its ability to promote cell cycle arrest and/or apoptosis [ 79 , 80 , 81 ]. The p53 pathway is often abrogated in cancer and sometimes this might depend on increased activity of its negative regulator MDM2 [ 82 ].…”

Smart Oncolytic Adenovirotherapy to Induce Killing of Cancer Cells and Elicit Antitumor Immunity

“…p53 and Cancer Cells Improved specificity for killing tumor cells has also been achieved by engineering synthetic circuitry to exploit the loss of checkpoint controls in cancer cells. The tumor suppressor p53 is a component of a checkpoint mechanism that regulates diverse cellular processes including, apoptosis, autophagy, and cell-cycle arrest in response to chromosome damage, errors in DNA replication or mitosis (Lees et al, 2021). In many types of human cancers, genetic alterations cause p53 to be inactivated (Tazawa et al, 2013).…”

HELLS Is Negatively Regulated by Wild-Type P53 in Liver Cancer by a Mechanism Involving P21 and FOXM1

“…More than 50% of all human cancers and 10–50% of HCC (depending on the etiology/risk factors including HBV, HCV and aflatoxin exposure) harbor TP53 mutations, highlighting the importance of P53 in (hepato-)carcinogenesis [ 4 , 6 ]. P53 responds to a variety of different cellular stresses (e.g., DNA damage, hypoxia, oncogene activation and telomere shortening) by activating or suppressing subsets of its numerous target genes to induce different cellular outcomes [ 4 , 5 , 7 ]. Mild stress levels lead to DNA repair or cell cycle arrest, allowing further survival of the cell, while extensive stress, like irreversible DNA damage, induces apoptosis or senescence [ 5 , 7 , 8 ].…”

“…P53 responds to a variety of different cellular stresses (e.g., DNA damage, hypoxia, oncogene activation and telomere shortening) by activating or suppressing subsets of its numerous target genes to induce different cellular outcomes [ 4 , 5 , 7 ]. Mild stress levels lead to DNA repair or cell cycle arrest, allowing further survival of the cell, while extensive stress, like irreversible DNA damage, induces apoptosis or senescence [ 5 , 7 , 8 ]. Among P53 target genes the cyclin-dependent kinase inhibitor P21/ CDKN1A represents one of the most important and best characterized direct P53 targets [ 4 ].…”