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Of the many cellular responses activated by TP53, which ones are critical for tumour suppression?

Abstract

The tumour suppressor TP53 is a master regulator of several cellular processes that collectively suppress tumorigenesis. The TP53 gene is mutated in ~50% of human cancers and these defects usually confer poor responses to therapy. The TP53 protein functions as a homo-tetrameric transcription factor, directly regulating the expression of ~500 target genes, some of them involved in cell death, cell cycling, cell senescence, DNA repair and metabolism. Originally, it was thought that the induction of apoptotic cell death was the principal mechanism by which TP53 prevents the development of tumours. However, gene targeted mice lacking the critical effectors of TP53-induced apoptosis (PUMA and NOXA) do not spontaneously develop tumours. Indeed, even mice lacking the critical mediators for TP53-induced apoptosis, G1/S cell cycle arrest and cell senescence, namely PUMA, NOXA and p21, do not spontaneously develop tumours. This suggests that TP53 must activate additional cellular responses to mediate tumour suppression. In this review, we will discuss the processes by which TP53 regulates cell death, cell cycling/cell senescence, DNA damage repair and metabolic adaptation, and place this in context of current understanding of TP53-mediated tumour suppression.

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Fig. 1: Induction of the BCL-2-regulated apoptotic pathway by TP53.
Fig. 2: Induction of cell senescence by TP53.
Fig. 3: Regulation of DNA damage repair by TP53.
Fig. 4: Proposed gene-targeting experiments to determine whether TP53-mediated upregulation of a specific direct TP53 target gene is responsible for tumour suppression.

Data availability

This review article does not present any new primary data.

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Acknowledgements

The authors thank the members of their laboratory and the Blood Cells and Blood Cancer Division for discussions, Catherine McLean for assistance with the preparation of this review and Peter Maltezos for drafting of figures. Work by the authors was supported by fellowships and grants from the Australian National Health and Medical Research Council (NHMRC) (Program Grant GNT1113133 to AS, Research Fellowships GNT1116937 to AS, Project Grants GNT1143105 to AS, Ideas Grants GNT 2002618 and GNT2001201 to GLK), the Leukemia & Lymphoma Society of America (Specialized Center of Research [SCOR] grant no. 7015-18 to AS and GLK), Victorian Cancer Agency (MCRF Fellowship 17028 to GLK), the estate of Anthony (Toni) Redstone OAM (AS and GLK), the Craig Perkins Cancer Research Foundation (GLK), and the Dyson Bequest (GLK). Work in the laboratories of the authors was made possible through Victorian State Government Operational Infrastructure Support (OIS) and Australian Government NHMRC Independent Research Institute Infrastructure Support (IRIIS) Scheme.

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AFT, GLK and AS conceived ideas for this review article, planned for its content, drafted figures and wrote the text.

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Correspondence to Andreas Strasser.

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Thomas, A.F., Kelly, G.L. & Strasser, A. Of the many cellular responses activated by TP53, which ones are critical for tumour suppression?. Cell Death Differ 29, 961–971 (2022). https://doi.org/10.1038/s41418-022-00996-z

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