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Shifting the paradigms for tumor suppression: lessons from the p53 field

Oncogene volume 40, pages 4281–4290 (2021)Cite this article

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Abstract

The TP53 gene continues to hold distinction as the most frequently mutated gene in cancer. Since its discovery in 1979, hundreds of research groups have devoted their efforts toward understanding why this gene is so frequently selected against by tumors, with the hopes of harnessing this information toward the improved therapy of cancer. The result is that this protein has been meticulously analyzed in tumor and normal cells, resulting in over 100,000 publications, with an average of 5000 papers published on p53 every year for the past decade. The journey toward understanding p53 function has been anything but straightforward; in fact, the field is notable for the numerous times that established paradigms not only have been shifted, but in fact have been shattered or reversed. In this review, we will discuss the manuscripts, or series of manuscripts, that have most radically changed our thinking about how this tumor suppressor functions, and we will delve into the emerging challenges for the future in this important area of research. It is hoped that this review will serve as a useful historical reference for those interested in p53, and a useful lesson on the need to be flexible in the face of established paradigms.

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Fig. 1: Transcription-dependent and -independent mechanisms of p53-mediated apoptosis.
Fig. 2: Ferroptosis is implicated in tumor suppression by p53.
Fig. 3: Mutant p53 shows paradoxical transformation and tumor suppression in GEMM models of intestinal neoplasia.

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Acknowledgements

This work was supported by the National Institutes of Health (R01 CA201430 and CA102184 to MEM, and K99 CA241367 to TB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors would like to apologize for all the investigators whose references could not be included in this article due to space constraints. The authors would also like to thank Keerthana Gnanapradeepan, Jessica C. Leung, and Joshua L. D. Parris in the Murphy lab for assistance and thoughtful discussions. Figures were created with BioRender.com under a paid subscription to AI.

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  1. Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA, USA

    Thibaut Barnoud, Alexandra Indeglia & Maureen E. Murphy

  2. Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Alexandra Indeglia

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Conception and design of the review: MEM. Generation of the figures: TB and AI. Drafting of manuscript: all. Proofing and revision of manuscript: all.

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Correspondence to Maureen E. Murphy.

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Barnoud, T., Indeglia, A. & Murphy, M.E. Shifting the paradigms for tumor suppression: lessons from the p53 field. Oncogene 40, 4281–4290 (2021). https://doi.org/10.1038/s41388-021-01852-z

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