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Cancers
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Targeting Therapies for the p53 Protein in Cancer Treatments
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Targeting Therapies for the p53 Protein in Cancer Treatments

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 17942

Special Issue Editor

Dr. Patricia A.J. Muller

E-Mail Website
Guest Editor
Cancer Research UK Manchester Institute, University of Manchester, Alderley Park SK10 4TG, UK
Interests: mutant p53; Rab Coupling protein; copper; lung cancer

Special Issue Information

The tumour suppressor protein p53 was discovered over 40 years ago and is arguably one of the most important proteins protecting us from developing tumours. In response to stress, p53 decides whether the stress is severe enough to destroy the cell or whether a repair program is initiated. Decreased p53 function strongly increases the chances of developing cancers and in more than half of all human cancers, the p53 gene is found to be mutated. Gene mutations lead to the complete loss of protein expression or to the expression of mutant forms of p53. Hundreds of different mutant p53 proteins are found in human cancers. Some display a loss of wildtype function, and others gain novel functions in promoting metastasis and chemoresistance, but the majority will display a combination of both to varying degrees. Although advances have been made recently, no strategies targeting p53 are in routine use in clinical practice. Many proposed targeting therapies aim to restore or increase wildtype p53 function. Others aim to make use of vulnerabilities caused by a loss of p53 function or mutant p53 expression.

In this Special Issue, we will discuss the differences between these targeting strategies and explore at what stage of drug development they are.

Dr. Patricia A.J. Muller
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • p53
  • p53 mutation
  • targeted therapy
  • reactivation
  • small molecules
  • MDM2/ MDMX inhibition

Published Papers (6 papers)

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Research

Jump to: Review

22 pages, 5242 KiB  
Article
p90RSK Regulates p53 Pathway by MDM2 Phosphorylation in Thyroid Tumors
by Immacolata Maietta, Francesca Del Peschio, Preziosa Buonocore, Eleonora Viscusi, Stefano Laudati, Giuseppe Iannaci, Michele Minopoli, Maria Letizia Motti and Valentina De Falco
Cancers 2023, 15(1), 121; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15010121 - 25 Dec 2022
Cited by 3 | Viewed by 2033
Abstract
The expression level of the tumor suppressor p53 is controlled by the E3 ubiquitin ligase MDM2 with a regulatory feedback loop, which allows p53 to upregulate its inhibitor MDM2. In this manuscript we demonstrated that p90RSK binds and phosphorylates MDM2 on serine 166 [...] Read more.
The expression level of the tumor suppressor p53 is controlled by the E3 ubiquitin ligase MDM2 with a regulatory feedback loop, which allows p53 to upregulate its inhibitor MDM2. In this manuscript we demonstrated that p90RSK binds and phosphorylates MDM2 on serine 166 both in vitro and in vivo by kinase assay, immunoblot, and co-immunoprecipitation assay; this phosphorylation increases the stability of MDM2 which in turn binds p53, ubiquitinating it and promoting its degradation by proteasome. A pharmacological inhibitor of p90RSK, BI-D1870, decreases MDM2 phosphorylation, and restores p53 function, which in turn transcriptionally increases the expression of cell cycle inhibitor p21 and of pro-apoptotic protein Bax and downregulates the anti-apoptotic protein Bcl-2, causing a block of cell proliferation, measured by a BrdU assay and growth curve, and promoting apoptosis, measured by a TUNEL assay. Finally, an immunohistochemistry evaluation of primary thyroid tumors, in which p90RSK is very active, confirms MDM2 stabilization mediated by p90RSK phosphorylation. Full article
(This article belongs to the Special Issue Targeting Therapies for the p53 Protein in Cancer Treatments)
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22 pages, 3605 KiB  
Article
MDMX Regulates Transcriptional Activity of p53 and FOXO Proteins to Stimulate Proliferation of Melanoma Cells
by Renier C. Heijkants, Amina F. A. S. Teunisse, Danielle de Jong, Kseniya Glinkina, Hailiang Mei, Szymon M. Kielbasa, Karoly Szuhai and Aart G. Jochemsen
Cancers 2022, 14(18), 4482; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14184482 - 15 Sep 2022
Cited by 2 | Viewed by 1688
Abstract
The tumor suppressor protein p53 has an important role in cell-fate determination. In cancer cells, the activity of p53 is frequently repressed by high levels of MDMX and/or MDM2. MDM2 is a ubiquitin ligase whose activity results in ubiquitin- and proteasome-dependent p53 degradation, [...] Read more.
The tumor suppressor protein p53 has an important role in cell-fate determination. In cancer cells, the activity of p53 is frequently repressed by high levels of MDMX and/or MDM2. MDM2 is a ubiquitin ligase whose activity results in ubiquitin- and proteasome-dependent p53 degradation, while MDMX inhibits p53-activated transcription by shielding the p53 transactivation domain. Interestingly, the oncogenic functions of MDMX appear to be more wide-spread than inhibition of p53. The present study aimed to elucidate the MDMX-controlled transcriptome. Therefore, we depleted MDMX with four distinct shRNAs from a high MDMX expressing uveal melanoma cell line and determined the effect on the transcriptome by RNAseq. Biological function analyses indicate the inhibition of the cell cycle regulatory genes and stimulation of cell death activating genes upon MDMX depletion. Although the inhibition of p53 activity clearly contributes to the transcription regulation controlled by MDMX, it appeared that the transcriptional regulation of multiple genes did not only rely on p53 expression. Analysis of gene regulatory networks indicated a role for Forkhead box (FOX) transcription factors. Depletion of FOXO proteins partly prevented the transcriptional changes upon MDMX depletion. Furthermore, depletion of FOXO proteins relatively diminished the growth inhibition upon MDMX knockdown, although the knockdown of the FOXO transcription factors also reduces cell growth. In conclusion, the p53-independent oncogenic functions of MDMX could be partially explained by its regulation of FOXO activity. Full article
(This article belongs to the Special Issue Targeting Therapies for the p53 Protein in Cancer Treatments)
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27 pages, 7964 KiB  
Article
Tipping Growth Inhibition into Apoptosis by Combining Treatment with MDM2 and WIP1 Inhibitors in p53WT Uterine Leiomyosarcoma
by Victoria Chamberlain, Yvette Drew and John Lunec
Cancers 2022, 14(1), 14; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010014 - 21 Dec 2021
Cited by 5 | Viewed by 3891
Abstract
As there is no optimal therapeutic strategy defined for women with advanced or recurrent uLMS, there is an urgent need for the discovery of novel, targeted approaches. One such area of interest is the pharmacological inhibition of the MDM2-p53 interaction with small-molecular-weight MDM2 [...] Read more.
As there is no optimal therapeutic strategy defined for women with advanced or recurrent uLMS, there is an urgent need for the discovery of novel, targeted approaches. One such area of interest is the pharmacological inhibition of the MDM2-p53 interaction with small-molecular-weight MDM2 inhibitors. Growth inhibition and cytotoxic assays were used to evaluate uLMS cell line responses to MDM2 inhibitors as single agents and in combination, qRT-PCR to assess transcriptional changes and Caspase-Glo 3/7 assay to detect apoptosis. RG7388 and HDM201 are potent, selective antagonists of the MDM2-p53 interaction that can effectively stabilise and activate p53 in a dose-dependent manner. GSK2830371, a potent and selective WIP1 phosphatase inhibitor, was shown to significantly potentiate the growth inhibitory effects of RG7388 and HDM201, and significantly increase the mRNA expression of p53 transcriptional target genes in a p53WT cell line at a concentration that has no growth inhibitory effects as a single agent. RG7388, HDM201 and GSK2830371 failed to induce apoptosis as single agents; however, a combination treatment tipped cells into apoptosis from senescence. These data present the possibility of MDM2 and WIP1 inhibitor combinations as a potential treatment option for p53WT uLMS patients that warrants further investigation. Full article
(This article belongs to the Special Issue Targeting Therapies for the p53 Protein in Cancer Treatments)
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Review

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15 pages, 464 KiB  
Review
The Development of p53-Targeted Therapies for Human Cancers
by Yier Lu, Meng Wu, Yang Xu and Lili Yu
Cancers 2023, 15(14), 3560; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15143560 - 10 Jul 2023
Cited by 6 | Viewed by 2100
Abstract
p53 plays a critical role in tumor suppression and is the most frequently mutated gene in human cancers. Most p53 mutants (mutp53) are missense mutations and are thus expressed in human cancers. In human cancers that retain wtp53, the wtp53 activities are downregulated [...] Read more.
p53 plays a critical role in tumor suppression and is the most frequently mutated gene in human cancers. Most p53 mutants (mutp53) are missense mutations and are thus expressed in human cancers. In human cancers that retain wtp53, the wtp53 activities are downregulated through multiple mechanisms. For example, the overexpression of the negative regulators of p53, MDM2/MDMX, can also efficiently destabilize and inactivate wtp53. Therefore, both wtp53 and mutp53 have become promising and intensively explored therapeutic targets for cancer treatment. Current efforts include the development of small molecule compounds to disrupt the interaction between wtp53 and MDM2/MDMX in human cancers expressing wtp53 and to restore wtp53-like activity to p53 mutants in human cancers expressing mutp53. In addition, a synthetic lethality approach has been applied to identify signaling pathways affected by p53 dysfunction, which, when targeted, can lead to cell death. While an intensive search for p53-targeted cancer therapy has produced potential candidates with encouraging preclinical efficacy data, it remains challenging to develop such drugs with good efficacy and safety profiles. A more in-depth understanding of the mechanisms of action of these p53-targeting drugs will help to overcome these challenges. Full article
(This article belongs to the Special Issue Targeting Therapies for the p53 Protein in Cancer Treatments)
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17 pages, 2369 KiB  
Review
GOF Mutant p53 in Cancers: A Therapeutic Challenge
by Lobsang Dolma and Patricia A. J. Muller
Cancers 2022, 14(20), 5091; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14205091 - 18 Oct 2022
Cited by 11 | Viewed by 3551
Abstract
TP53 is mutated in the majority of human cancers. Mutations can lead to loss of p53 expression or expression of mutant versions of the p53 protein. These mutant p53 proteins have oncogenic potential. They can inhibit any remaining WTp53 in a dominant negative [...] Read more.
TP53 is mutated in the majority of human cancers. Mutations can lead to loss of p53 expression or expression of mutant versions of the p53 protein. These mutant p53 proteins have oncogenic potential. They can inhibit any remaining WTp53 in a dominant negative manner, or they can acquire new functions that promote tumour growth, invasion, metastasis and chemoresistance. In this review we explore some of the mechanisms that make mutant p53 cells resistant to chemotherapy. As mutant p53 tumours are resistant to many traditional chemotherapies, many have sought to explore new ways of targeting mutant p53 tumours and reinstate chemosensitivity. These approaches include targeting of mutant p53 stability, mutant p53 binding partners and downstream pathways, p53 vaccines, restoration of WTp53 function, and WTp53 gene delivery. The current advances and challenges of these strategies are discussed. Full article
(This article belongs to the Special Issue Targeting Therapies for the p53 Protein in Cancer Treatments)
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20 pages, 2090 KiB  
Review
p53 Isoforms as Cancer Biomarkers and Therapeutic Targets
by Liuqun Zhao and Suparna Sanyal
Cancers 2022, 14(13), 3145; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133145 - 27 Jun 2022
Cited by 12 | Viewed by 3595
Abstract
This review aims to summarize the implications of the major isoforms of the tumor suppressor protein p53 in aggressive cancer development. The current knowledge of p53 isoforms, their involvement in cell-signaling pathways, and their interactions with other cellular proteins or factors suggests the [...] Read more.
This review aims to summarize the implications of the major isoforms of the tumor suppressor protein p53 in aggressive cancer development. The current knowledge of p53 isoforms, their involvement in cell-signaling pathways, and their interactions with other cellular proteins or factors suggests the existence of an intricate molecular network that regulates their oncogenic function. Moreover, existing literature about the involvement of the p53 isoforms in various cancers leads to the proposition of therapeutic solutions by altering the cellular levels of the p53 isoforms. This review thus summarizes how the major p53 isoforms Δ40p53α/β/γ, Δ133p53α/β/γ, and Δ160p53α/β/γ might have clinical relevance in the diagnosis and effective treatments of cancer. Full article
(This article belongs to the Special Issue Targeting Therapies for the p53 Protein in Cancer Treatments)
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