Gain-of-function mutant p53: history and speculation

Bargonetti, Jill; Prives, Carol

doi:10.1093/jmcb/mjz067

Cited by 71 publications

(73 citation statements)

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“…Mutant p53 proteins not only lose their native tumor suppressive functions but often gain additional oncogenic functions and essentially behave as an oncogene (Freed-Pastor and Prives, 2012; Oren and Rotter, 2010; Rivlin et al, 2011). p53 mutations enhance the proliferative and tumorigenic potential of the cells contributing to various stages of tumor progression and increased anti-cancer drug resistance (Bargonetti and Prives, 2019;Stein et al, 2019). Hotspot mutations in p53 show a common tendency to destabilize/misfold the native conformation of the protein (Wilcken et al, 2012), leading to the formation of aggregates of inactive p53, which are sequestered and targeted by the proteasomal degradation machinery (Ano Bom et al, 2012;Levy et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Induction of intracellular wild-type p53 amyloids leading to cellular transformation and tumor formation in mice

Navalkar

Pandey

Singh

et al. 2020

Preprint

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Tumor suppressor p53 mutations, with subsequent loss-of-tumor suppressive function and gainof oncogenic functions, are associated with more than 50% of human cancers. Aggregation and amyloid formation are also mechanisms by which wild type and mutant p53 might be involved in cancer, but the direct evidence of how aggregated p53 acts as an oncogene is lacking. In this study, we directly demonstrate that wild-type p53 amyloid formation imparts oncogenic properties to normal cells. Cells with p53 amyloids show enhanced survival, apoptotic resistance with increased proliferation and migration rates. The tumorigenic potential of p53 amyloid transformed cells is further confirmed in a mice xenograft model, wherein the tumor showed p53 amyloid aggregates. Gene-expression analysis and proteomic profiling suggest that p53 amyloid formation triggers aberrant expression of pro-oncogenes while downregulating the tumorsuppressive genes. Interestingly, disaggregating p53 rescues the cellular transformation and also inhibits tumor development in mice. We propose that wild-type p53 amyloid formation can potentially contribute to the initiation of tumor development.

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Section: Introductionmentioning

confidence: 99%

Induction of intracellular wild-type p53 amyloids leading to cellular transformation and tumor formation in mice

Navalkar

Pandey

Singh

et al. 2020

Preprint

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“…Most of the missense mutations occur in the p53 DNA-binding region and can be classified as either contact mutations (as p53R248 and p53R273 interfere directly with DNA binding) or conformational mutations (as p53R175 induces local or global conformational distortions) [5,9].Six hotspot mutations are the most represented in the cancers. These include R175, G245, R248, R249, R273, and R282, which make up about 30% of all mutations in TP53 covering all human cancer types [8][9][10]. However, due to cancer genome sequencing tools, many other different TP53 mutations have been discovered.…”

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confidence: 99%

“…However, due to cancer genome sequencing tools, many other different TP53 mutations have been discovered. mut-p53 GOF has been demonstrated by numerous cell-based experiments such as by ectopic expression of mut-p53 proteins in p53-null human tumor cells or knockdown of endogenous mut-p53 in cells containing only one allele of mutant p53, as well as in mutant p53 knock-in mouse models [5,[8][9][10]. Genome sequencencing has highlighted that more than 91% of TP53-mutant cancers exhibit loss of the second allele (LOH) by mutation or DNA deletion [11].Many mut-p53 GOF activities have been identified as tumor cell proliferation, survival, migration and invasion, enhancing chemoresistance, disrupting proper tissue architecture, inducing cancer metabolism (Warburg effect and lipid metabolism), and increasing genomic instability and mitochondrial dysfunction [5,[10][11][12][13][14][15] (Figure 1).…”

mentioning

confidence: 99%

“…Six hotspot mutations are the most represented in the cancers. These include R175, G245, R248, R249, R273, and R282, which make up about 30% of all mutations in TP53 covering all human cancer types [8][9][10]. However, due to cancer genome sequencing tools, many other different TP53 mutations have been discovered.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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The Impact of Mutant p53 in the Non-Coding RNA World

Agostino

2020

Biomolecules

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Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), micro RNAs (miRNAs), and extracellular RNAs (exRNAs) are new groups of RNAs with regulation activities that have low or no protein-coding ability. Emerging evidence suggests that deregulated expression of these non-coding RNAs is associated with the induction and progression of diverse tumors throughout epigenetic, transcriptional, and post-transcriptional modifications. A consistent number of non-coding RNAs (ncRNAs) has been shown to be regulated by p53, the most important tumor suppressor of the cells frequently mutated in human cancer. It has been shown that some mutant p53 proteins are associated with the loss of tumor suppressor activity and the acquisition of new oncogenic functions named gain-of-function activities. In this review, we highlight recent lines of evidence suggesting that mutant p53 is involved in the expression of specific ncRNAs to gain oncogenic functions through the creation of a complex network of pathways that influence each other.Biomolecules 2020, 10, 472 2 of 15 heterotetrameric mut-p53/wt-p53 complex can inhibit the function of the remaining wt-p53 in tumor suppression [8,9]. Most of the missense mutations occur in the p53 DNA-binding region and can be classified as either contact mutations (as p53R248 and p53R273 interfere directly with DNA binding) or conformational mutations (as p53R175 induces local or global conformational distortions) [5,9].Six hotspot mutations are the most represented in the cancers. These include R175, G245, R248, R249, R273, and R282, which make up about 30% of all mutations in TP53 covering all human cancer types [8][9][10]. However, due to cancer genome sequencing tools, many other different TP53 mutations have been discovered. mut-p53 GOF has been demonstrated by numerous cell-based experiments such as by ectopic expression of mut-p53 proteins in p53-null human tumor cells or knockdown of endogenous mut-p53 in cells containing only one allele of mutant p53, as well as in mutant p53 knock-in mouse models [5,[8][9][10]. Genome sequencencing has highlighted that more than 91% of TP53-mutant cancers exhibit loss of the second allele (LOH) by mutation or DNA deletion [11].Many mut-p53 GOF activities have been identified as tumor cell proliferation, survival, migration and invasion, enhancing chemoresistance, disrupting proper tissue architecture, inducing cancer metabolism (Warburg effect and lipid metabolism), and increasing genomic instability and mitochondrial dysfunction [5,[10][11][12][13][14][15] (Figure 1).

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FGFR3 alterations in bladder cancer: Sensitivity and resistance to targeted therapies

Noeraparast,

Krajina,

Pichler

et al. 2024

Cancer Communications

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In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non‐muscle‐invasive and muscle‐invasive forms of the disease. FGFR3 mutations in up to half of BLCAs play a well‐established role in tumorigenesis, shaping distinct tumor initiation patterns and impacting the tumor microenvironment (TME). Emphasizing the importance of considering epithelial‐mesenchymal transition profile and TME status, we revisit their relevance in predicting responses to immune checkpoint inhibitors in FGFR3‐mutated BLCAs. This writing highlights the initially promising yet transient efficacy of the FGFR inhibitor Erdafitinib on FGFR3‐mutated BLCA, stressing the pressing need to unravel resistance mechanisms and identify co‐targets for future combinatorial studies. A thorough analysis of recent preclinical and clinical evidence reveals resistance mechanisms, including secondary mutations, epigenetic alterations in pathway effectors, phenotypic heterogeneity, and population‐specific variations within FGFR3 mutational status. Lastly, we discuss the potential of combinatorial treatments and concepts like synthetic lethality for discovering more effective targeted therapies against FGFR3‐mutated BLCA.

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Gain-of-function mutant p53: history and speculation

Cited by 71 publications

References 53 publications

Induction of intracellular wild-type p53 amyloids leading to cellular transformation and tumor formation in mice

Induction of intracellular wild-type p53 amyloids leading to cellular transformation and tumor formation in mice

The Impact of Mutant p53 in the Non-Coding RNA World

FGFR3 alterations in bladder cancer: Sensitivity and resistance to targeted therapies

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