Do Mutations Turn p53 into an Oncogene?

Pitolli, Consuelo; Wang, Ying; Mancini, Mara; Shi, Yufang; Melino, Gerry; Amelio, Ivano

doi:10.3390/ijms20246241

Cited by 62 publications

(51 citation statements)

References 130 publications

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“…An additional critical aspect of the mutations in p53 is the frequently observed protein products. Eighty percent of p53 mutations are missense, leading to generation of neomorphic proteins 25,26 , the function of which has been associated with deregulation of a wide range of physiological cellular signalling processes 14 and interacting partners, including its family members, p63 [27][28][29] and p73 [30][31][32][33][34] . These mechanisms are thought to support tumorigenesis, leading to the postulation of the gain-offunction (GOF) theory in p53 mutation 26 .…”

Section: Questionsmentioning

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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Section: Questionsmentioning

confidence: 99%

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

Amelio

Melino

2020

Cell Death Discov.

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“…Mutant p53 proteins can form heterotetramers with WT p53, hampering the function of the latter in tumor suppression (21). The primary outcome of TP53 mutations leading to loss of WT p53 functions is the abrogation of its intrinsic tumor suppressive responses such as senescence and apoptosis, while gain-of-function mutant p53 proteins enhance tumor progression, metastatic potential, and drug resistance, greatly contributing to the malignant cellular phenotype (22)(23)(24).…”

Section: Defensive Strategy: Small Molecule Re-activatorsmentioning

confidence: 99%

Key Players in the Mutant p53 Team: Small Molecules, Gene Editing, Immunotherapy

et al. 2020

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The transcription factor p53 is a key tumor suppressor that is inactivated in almost all cancers due to either point mutations in the TP53 gene or overexpression of its negative regulators. The p53 protein is known as the "cellular gatekeeper" for its roles in facilitating DNA repair, cell cycle arrest or apoptosis upon DNA damage. Most p53 mutations are missense and result in either structural destabilization of the protein, causing its partial unfolding and deactivation under physiological conditions, or impairment of its DNA-binding properties. Tumor cells with p53 mutations are generally more immunogenic due to "hot spot" neoantigens that instigate the immune system response. In this review, we discuss the key therapeutic strategies targeting mutant p53 tumors, including classical approaches based on small molecule intervention and emerging technologies such as gene editing and T cell immunotherapy.

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“…The TP53 gene that encodes p53 protein is mutated in approximately half of all human cancers, which makes it a highly desirable target for gene-editing tools, e.g., to reverse pathogenic mutations back to the wild-type (WT) state [ 58 ].…”

Section: Crispr/cas9 System and Tp53 Pathway Gementioning

confidence: 99%

Therapeutic Editing of the TP53 Gene: Is CRISPR/Cas9 an Option?

Mirgayazova

Khadiullina

Chasov

et al. 2020

Genes

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The TP53 gene encodes the transcription factor and oncosuppressor p53 protein that regulates a multitude of intracellular metabolic pathways involved in DNA damage repair, cell cycle arrest, apoptosis, and senescence. In many cases, alterations (e.g., mutations of the TP53 gene) negatively affect these pathways resulting in tumor development. Recent advances in genome manipulation technologies, CRISPR/Cas9, in particular, brought us closer to therapeutic gene editing for the treatment of cancer and hereditary diseases. Genome-editing therapies for blood disorders, blindness, and cancer are currently being evaluated in clinical trials. Eventually CRISPR/Cas9 technology is expected to target TP53 as the most mutated gene in all types of cancers. A majority of TP53 mutations are missense which brings immense opportunities for the CRISPR/Cas9 system that has been successfully used for correcting single nucleotides in various models, both in vitro and in vivo. In this review, we highlight the recent clinical applications of CRISPR/Cas9 technology for therapeutic genome editing and discuss its perspectives for editing TP53 and regulating transcription of p53 pathway genes.

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Do Mutations Turn p53 into an Oncogene?

Cited by 62 publications

References 130 publications

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

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

Key Players in the Mutant p53 Team: Small Molecules, Gene Editing, Immunotherapy

Therapeutic Editing of the TP53 Gene: Is CRISPR/Cas9 an Option?

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