It takes a team: a gain-of-function story of p53-R249S

Huai, Wang; Liao, Peng; Zeng, Shelya X.; Lu, Hua

doi:10.1093/jmcb/mjy086

Cited by 36 publications

(41 citation statements)

References 85 publications

(123 reference statements)

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“…Although the traditional six hotspots can be detected in almost all cancers with p53 mutations, certain cancers seem to have a predisposition for certain mutants. An example of this is hepatocellular carcinoma (HCC), in which there appears to be a selection for expression of one hotspot, mutant p53 R249S [123]. Remarkably, homozygous mutant p53 R246S (the mouse equivalent of R249S) expressing mice did not display tumourigenesis, as seen in the R172H (the equivalent of R175H) mice.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

The Diverse Functions of Mutant 53, Its Family Members and Isoforms in Cancer

Hall

Müller

2019

IJMS

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The p53 family of proteins has grown substantially over the last 40 years. It started with p53, then p63, p73, isoforms and mutants of these proteins. The function of p53 as a tumour suppressor has been thoroughly investigated, but the functions of all isoforms and mutants and the interplay between them are still poorly understood. Mutant p53 proteins lose p53 function, display dominant-negative (DN) activity and display gain-of-function (GOF) to varying degrees. GOF was originally attributed to mutant p53′s inhibitory function over the p53 family members p63 and p73. It has become apparent that this is not the only way in which mutant p53 operates as a large number of transcription factors that are not related to p53 are activated on mutant p53 binding. This raises the question to what extent mutant p53 binding to p63 and p73 plays a role in mutant p53 GOF. In this review, we discuss the literature around the interaction between mutant p53 and family members, including other binding partners, the functional consequences and potential therapeutics.

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Section: Conclusion and Discussionmentioning

confidence: 99%

The Diverse Functions of Mutant 53, Its Family Members and Isoforms in Cancer

Hall

Müller

2019

IJMS

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“…The genetic hallmark of AFB1 exposure and HCC risk is a specific mutation as a single-base substitution at the third base of codon 249 in the TP53 gene. This mutation replaces an arginine by a serine (R249S) [72][73][74]. In addition, genetic polymorphism in the enzymes of activation (CYP enzymes) and deactivation (glutathione S-transferase) of pro-mutagenic aflatoxins may affect the level of pro-mutagenic aflatoxins and consequently the HCC risk [65].…”

Section: (B) Aflatoxinsmentioning

confidence: 99%

Hepatocellular Carcinoma (HCC) in Egypt: A comprehensive overview

Rashed

Kandeil

Mahmoud

et al. 2020

J Egypt Natl Canc Inst

208

163

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Background: Worldwide, hepatocellular carcinoma (HCC) is a universal problem and its epidemiological data showed variation from place to place. Hepatocellular carcinoma (HCC) is the sixth and fourth common cancer in worldwide and Egypt, respectively. Egypt ranks the third and 15 th most populous country in Africa and worldwide, respectively. The aim of this review is to compare the status of HCC in Egypt to that in the worldwide from different issues; risk factors, screening and surveillance, diagnosis and treatment, prevention, as well as research strategy. Main body: The risk factors for HCC in Egypt are of great importance to be reported. The risk factor for HCC are either environmental-or host/genetic-related risk factors. In the last years, there is a tangible improvement of both screening and surveillance strategies of HCC in Egypt. The unprecedented national screening campaign launched by the end of 2018 is a mirror image of this improvement. While the improvement of the HCC prevention requires the governmental health administration to implement health policies. Although the diagnosis of Egyptian HCC patients follows the international guidelines but HCC treatment options are limited in terms of cost. In addition, there are limited Egyptian reports about HCC survival and relapse. Both basic and clinical HCC research in Egypt are still limited compared to worldwide. Short conclusion: Deep analysis and understanding of factors affecting HCC burden variation worldwide help in customization of efforts exerted to face HCC in different countries especially large country like Egypt. Overall, the presence of a research strategy to fight HCC in Egyptian patients will help in the optimum allocation of available resources to reduce the numbers of HCC cases and deaths and to improve the quality of life.

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“…mtp53-R273H bolsters the mevalonate pathway by interacting with the sterol regulatory element binding transcription factors (SREBFs), leading to enhanced biosynthesis of sterols and isoprenoids and thus cancer progression [74]. It has been recently described that a liver cancer-derived hotspot p53 mutant, R249S, can be phosphorylated by CDK4/Cyclin D and translocate into the nucleus, where it empowers the c-Myc-induced ribosome biogenesis and hepatocellular carcinoma cell proliferation [75,76]. Like wtp53, mtp53 also performs its oncogenic function independent of transcriptional regulation.…”

Section: P53 Mutation Endorses Cancer Developmentmentioning

confidence: 99%

The Janus Face of p53-Targeting Ubiquitin Ligases

Hao

Chen

Zhou

2020

Cells

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The tumor suppressor p53 prevents tumorigenesis and cancer progression by maintaining genomic stability and inducing cell growth arrest and apoptosis. Because of the extremely detrimental nature of wild-type p53, cancer cells usually mutate the TP53 gene in favor of their survival and propagation. Some of the mutant p53 proteins not only lose the wild-type activity, but also acquire oncogenic function, namely “gain-of-function”, to promote cancer development. Growing evidence has revealed that various E3 ubiquitin ligases are able to target both wild-type and mutant p53 for degradation or inactivation, and thus play divergent roles leading to cancer cell survival or death in the context of different p53 status. In this essay, we reviewed the recent progress in our understanding of the p53-targeting E3 ubiquitin ligases, and discussed the potential clinical implications of these E3 ubiquitin ligases in cancer therapy.

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It takes a team: a gain-of-function story of p53-R249S

Cited by 36 publications

References 85 publications

The Diverse Functions of Mutant 53, Its Family Members and Isoforms in Cancer

The Diverse Functions of Mutant 53, Its Family Members and Isoforms in Cancer

Hepatocellular Carcinoma (HCC) in Egypt: A comprehensive overview

The Janus Face of p53-Targeting Ubiquitin Ligases

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