Reviewing the future of the P53 field

Levine, Arnold J.

doi:10.1038/cdd.2017.181

Cited by 33 publications

(32 citation statements)

References 9 publications

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“…The signaling triggered by GOF proteins might underlie the cancers addiction to mutant p53, and this opens potential therapeutic strategies to target aggressive late stage cancers. While a better understanding of GOF mechanisms is still needed [129,135], a pragmatic effort should also be invested in, developing approaches to promote degradation of mutant p53 to treat lethal cancers.…”

Section: Discussionmentioning

confidence: 99%

Do Mutations Turn p53 into an Oncogene?

Pitolli

Wang

Mancini

et al. 2019

IJMS

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The key role of p53 as a tumor suppressor became clear when it was realized that this gene is mutated in 50% of human sporadic cancers, and germline mutations expose carriers to cancer risk throughout their lifespan. Mutations in this gene not only abolish the tumor suppressive functions of p53, but also equip the protein with new pro-oncogenic functions. Here, we review the mechanisms by which these new functions gained by p53 mutants promote tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Do Mutations Turn p53 into an Oncogene?

Pitolli

Wang

Mancini

et al. 2019

IJMS

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“…While a massive effort in drug development against p53 mutant tumours has been invested in the two past decades, the outcome is very soon expected to be delivered. This should also help in understanding how feasible the approach is and direct efforts for future investments 68 . Fig.…”

Section: Conclusion: P53 Mutants: One Gene Many Proteins In Many Conmentioning

confidence: 99%

Context is everything: extrinsic signalling and gain-of-function p53 mutants

Amelio

Melino

2020

Cell Death Discov.

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The TP53 genomic locus is a target of mutational events in at least half of cancers. Despite several decades of study, a full consensus on the relevance of the acquisition of p53 gain-of-function missense mutants has not been reached. Depending on cancer type, type of mutations and other unidentified factors, the relevance for tumour development and progression of the oncogenic signalling directed by p53 mutants might significantly vary, leading to inconsistent observations that have fuelled a long and fierce debate in the field. Here, we discuss how interaction with the microenvironment and stressors might dictate the gain-of-function effects exerted by individual mutants. We report evidence from the most recent literature in support of the context dependency of p53 mutant biology. This perspective article aims to raise a discussion in the field on the relevance that context might have on p53 gain-offunction mutants, assessing whether this should generally be considered a cell non-autonomous process. Facts • Mutant p53 GOF effects have been shown to vary in different settings, potentially depending on cancer types, experimental models and conditions. • Reciprocal interaction between microenvironment and mutant p53 GOF effects exists.

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“…[1][2][3][4] p53 is also a translational regulator. It is a key regulatory protein, especially as a transcription factor, and participates in diverse cellular processes, such as cell cycle arrest, DNA repair, and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…It is a key regulatory protein, especially as a transcription factor, and participates in diverse cellular processes, such as cell cycle arrest, DNA repair, and apoptosis. [1][2][3][4] p53 is also a translational regulator. 5 Activities of p53, such as efficient and specific binding to p53 cis-elements within target promoter sequences, as well as tissue-, time-, and stimulus-specific binding of numerous coactivators and modifiers, are regulated by its abundance, post-translational modifications, and protein-protein interactions; all of which are influenced by a number of signaling pathways converging on p53.…”

Section: Introductionmentioning

confidence: 99%

Calpain-mediated cleavage of p53 in human cytomegalovirus-infected lung fibroblasts

et al. 2018

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Endogenous fragments of p53 protein were identified in human cytomegalovirus (HCMV)‐infected human lung fibroblasts, particularly a 44‐kDa N‐terminal fragment [hereafter referred to as p53(ΔCp44)], generated via calpain cleavage. The fragment abundance increased in a biphasic manner, peaking at 6‐9 hours and 48 hours post infection. Treatment of LU cells with calpain inhibitors eliminated most detectable p53 fragments. In cell‐free experiments, exogenous m‐calpain cleavage generated p53(ΔCp44). Attempts to preserve p53 proteins by treating cells with the calpain inhibitor E64d for 6 hours before harvesting increased the sensitivity of p53 to calpain cleavage. p53 in mock‐infected cell lysates was much more sensitive to cleavage and degradation by exogenous calpain than that in HCMV‐infected cells. The proteasome inhibitor MG132 stabilized p53(ΔCp44), particularly in mock‐infected cells. p53(ΔCp44) appeared to be tightly associated with a chromatin‐rich fraction. The abundance of p53β was unchanged over a 96‐h time course and very similar in mock‐ and HCMV‐infected cells, making it unlikely that p53(ΔCp44) was p53β. The biological activities of this and other fragments lacking C‐terminal sequences are unknown, but deserve further investigation, given the association of p53(ΔCp44) with the chromatin‐rich (or buffer C insoluble) fraction in HCMV‐infected cells.

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Reviewing the future of the P53 field

Cited by 33 publications

References 9 publications

Do Mutations Turn p53 into an Oncogene?

Do Mutations Turn p53 into an Oncogene?

Context is everything: extrinsic signalling and gain-of-function p53 mutants

Calpain-mediated cleavage of p53 in human cytomegalovirus-infected lung fibroblasts

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