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Cancers
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P53 and Hallmarks of Cancer
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P53 and Hallmarks of Cancer

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

Deadline for manuscript submissions: closed (10 December 2020) | Viewed by 24121

Special Issue Editor

Prof. Dr. Regine Schneider-Stock

E-Mail Website
Guest Editor
Experimental Tumor Pathology, Institute of Pathology, University Hospital Erlangen, Universitätsstraße, Erlangen, Germany
Interests: colon cancer metastasis; CAM model; tumor cell invasion; tumor invasion front
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

P53 mutations are found in approximately 50% of cancer. The majority of p53 mutations are missense-type mutations within hot spots in the DNA-binding region.

Although we know a lot about wildtype p53 the associations between different p53 mutation types and cancer hallmarks such as repair, proliferation, cell death and resistance mechanisms, epithelial-to-mesenchymal transition (EMT), stromal interaction with immune escape, or metastasis are still not completely understood. In the last years we have learnt that p53 mutations not only result in loss of tumor suppressor function but rather create new oncogenic p53 proteins binding to new gene targets and having tumor promoting functions.

In this Special Issue, we will focus on mutant p53 and its role in initiation, progression, and metastasis of cancer. Studies on animal models addressing the function of mutant p53 and reviews or research papers that focus on the mechanisms of action of p53 mutations in different tumor stages and subtypes are particularly welcome.

Prof. Dr. Regine Schneider-Stock
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 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 mutations
  • Cancer
  • Hallmarks of cancer
  • Signaling pathways
  • In vitro and in vivo models
  • Clinics (prognosis, therapy)

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Published Papers (6 papers)

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Research

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16 pages, 609 KiB  
Article
Functional Classification of TP53 Mutations in Acute Myeloid Leukemia
by Sayantanee Dutta, Gudrun Pregartner, Frank G. Rücker, Ellen Heitzer, Armin Zebisch, Lars Bullinger, Andrea Berghold, Konstanze Döhner and Heinz Sill
Cancers 2020, 12(3), 637; https://doi.org/10.3390/cancers12030637 - 10 Mar 2020
Cited by 45 | Viewed by 5376
Abstract
Mutations of the TP53 gene occur in a subset of patients with acute myeloid leukemia (AML) and confer an exceedingly adverse prognosis. However, whether different types of TP53 mutations exert a uniformly poor outcome has not been investigated yet. Here, we addressed this [...] Read more.
Mutations of the TP53 gene occur in a subset of patients with acute myeloid leukemia (AML) and confer an exceedingly adverse prognosis. However, whether different types of TP53 mutations exert a uniformly poor outcome has not been investigated yet. Here, we addressed this issue by analyzing data of 1537 patients intensively treated within protocols of the German-Austrian AML study group. We classified TP53 mutations depending on their impact on protein structure and according to the evolutionary action (EAp53) score and the relative fitness score (RFS). In 98/1537 (6.4%) patients, 108 TP53 mutations were detected. While the discrimination depending on the protein structure and the EAp53 score did not show a survival difference, patients with low-risk and high-risk AML-specific RFS showed a different overall survival (OS; median, 12.9 versus 5.5 months, p = 0.017) and event-free survival (EFS; median, 7.3 versus 5.2 months, p = 0.054). In multivariable analyses adjusting for age, gender, white blood cell count, cytogenetic risk, type of AML, and TP53 variant allele frequency, these differences were statistically significant for both OS (HR, 2.14; 95% CI, 1.15–4.0; p = 0.017) and EFS (HR, 1.97; 95% CI, 1.06–3.69; p = 0.033). We conclude that the AML-specific RFS is of prognostic value in patients with TP53-mutated AML and a useful tool for therapeutic decision-making. Full article
(This article belongs to the Special Issue P53 and Hallmarks of Cancer)
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Review

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41 pages, 3351 KiB  
Review
Regulation of p53 by E3s
by Mengwu Pan and Christine Blattner
Cancers 2021, 13(4), 745; https://doi.org/10.3390/cancers13040745 - 11 Feb 2021
Cited by 17 | Viewed by 4137
Abstract
More than 40 years of research on p53 have given us tremendous knowledge about this protein. Today we know that p53 plays a role in different biological processes such as proliferation, invasion, pluripotency, metabolism, cell cycle control, ROS (reactive oxygen species) production, apoptosis, [...] Read more.
More than 40 years of research on p53 have given us tremendous knowledge about this protein. Today we know that p53 plays a role in different biological processes such as proliferation, invasion, pluripotency, metabolism, cell cycle control, ROS (reactive oxygen species) production, apoptosis, inflammation and autophagy. In the nucleus, p53 functions as a bona-fide transcription factor which activates and represses transcription of a number of target genes. In the cytoplasm, p53 can interact with proteins of the apoptotic machinery and by this also induces cell death. Despite being so important for the fate of the cell, expression levels of p53 are kept low in unstressed cells and the protein is largely inactive. The reason for the low expression level is that p53 is efficiently degraded by the ubiquitin-proteasome system and the vast inactivity of the tumor suppressor protein under normal growth conditions is due to the absence of activating and the presence of inactivating posttranslational modifications. E3s are important enzymes for these processes as they decorate p53 with ubiquitin and small ubiquitin-like proteins and by this control p53 degradation, stability and its subcellular localization. In this review, we provide an overview about E3s that target p53 and discuss the connection between p53, E3s and tumorigenesis. Full article
(This article belongs to the Special Issue P53 and Hallmarks of Cancer)
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19 pages, 720 KiB  
Review
The Interactions of DNA Repair, Telomere Homeostasis, and p53 Mutational Status in Solid Cancers: Risk, Prognosis, and Prediction
by Pavel Vodicka, Ladislav Andera, Alena Opattova and Ludmila Vodickova
Cancers 2021, 13(3), 479; https://doi.org/10.3390/cancers13030479 - 27 Jan 2021
Cited by 26 | Viewed by 3828
Abstract
The disruption of genomic integrity due to the accumulation of various kinds of DNA damage, deficient DNA repair capacity, and telomere shortening constitute the hallmarks of malignant diseases. DNA damage response (DDR) is a signaling network to process DNA damage with importance for [...] Read more.
The disruption of genomic integrity due to the accumulation of various kinds of DNA damage, deficient DNA repair capacity, and telomere shortening constitute the hallmarks of malignant diseases. DNA damage response (DDR) is a signaling network to process DNA damage with importance for both cancer development and chemotherapy outcome. DDR represents the complex events that detect DNA lesions and activate signaling networks (cell cycle checkpoint induction, DNA repair, and induction of cell death). TP53, the guardian of the genome, governs the cell response, resulting in cell cycle arrest, DNA damage repair, apoptosis, and senescence. The mutational status of TP53 has an impact on DDR, and somatic mutations in this gene represent one of the critical events in human carcinogenesis. Telomere dysfunction in cells that lack p53-mediated surveillance of genomic integrity along with the involvement of DNA repair in telomeric DNA regions leads to genomic instability. While the role of individual players (DDR, telomere homeostasis, and TP53) in human cancers has attracted attention for some time, there is insufficient understanding of the interactions between these pathways. Since solid cancer is a complex and multifactorial disease with considerable inter- and intra-tumor heterogeneity, we mainly dedicated this review to the interactions of DNA repair, telomere homeostasis, and TP53 mutational status, in relation to (a) cancer risk, (b) cancer progression, and (c) cancer therapy. Full article
(This article belongs to the Special Issue P53 and Hallmarks of Cancer)
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21 pages, 736 KiB  
Review
Making Connections: p53 and the Cathepsin Proteases as Co-Regulators of Cancer and Apoptosis
by Surinder M. Soond, Lyudmila V. Savvateeva, Vladimir A. Makarov, Neonila V. Gorokhovets, Paul A. Townsend and Andrey A. Zamyatnin, Jr.
Cancers 2020, 12(11), 3476; https://doi.org/10.3390/cancers12113476 - 22 Nov 2020
Cited by 11 | Viewed by 3674
Abstract
While viewed as the “guardian of the genome”, the importance of the tumor suppressor p53 protein has increasingly gained ever more recognition in modulating additional modes of action related to cell death. Slowly but surely, its importance has evolved from a mutated genetic [...] Read more.
While viewed as the “guardian of the genome”, the importance of the tumor suppressor p53 protein has increasingly gained ever more recognition in modulating additional modes of action related to cell death. Slowly but surely, its importance has evolved from a mutated genetic locus heavily implicated in a wide array of cancer types to modulating lysosomal-mediated cell death either directly or indirectly through the transcriptional regulation of the key signal transduction pathway intermediates involved in this. As an important step in determining the fate of cells in response to cytotoxicity or during stress response, lysosomal-mediated cell death has also become strongly interwoven with the key components that give the lysosome functionality in the form of the cathepsin proteases. While a number of articles have been published highlighting the independent input of p53 or cathepsins to cellular homeostasis and disease progression, one key area that warrants further focus is the regulatory relationship that p53 and its isoforms share with such proteases in regulating lysosomal-mediated cell death. Herein, we review recent developments that have shaped this relationship and highlight key areas that need further exploration to aid novel therapeutic design and intervention strategies. Full article
(This article belongs to the Special Issue P53 and Hallmarks of Cancer)
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21 pages, 563 KiB  
Review
Integrative p53, micro-RNA and Cathepsin Protease Co-Regulatory Expression Networks in Cancer
by Surinder M. Soond, Maria V. Kozhevnikova, Paul A. Townsend and Andrey A. Zamyatnin, Jr.
Cancers 2020, 12(11), 3454; https://doi.org/10.3390/cancers12113454 - 20 Nov 2020
Cited by 5 | Viewed by 2737
Abstract
As the direct regulatory role of p53 and some of its isoform proteins are becoming established in modulating gene expression in cancer research, another aspect of this mode of gene regulation that has captured significant interest over the years is the mechanistic interplay [...] Read more.
As the direct regulatory role of p53 and some of its isoform proteins are becoming established in modulating gene expression in cancer research, another aspect of this mode of gene regulation that has captured significant interest over the years is the mechanistic interplay between p53 and micro-RNA transcriptional regulation. The input of this into modulating gene expression for some of the cathepsin family members has been viewed as carrying noticeable importance based on their biological effects during normal cellular homeostasis and cancer progression. While this area is still in its infancy in relation to general cathepsin gene regulation, we review the current p53-regulated micro-RNAs that are generating significant interest through their regulation of cathepsin proteases, thereby strengthening the link between activated p53 forms and cathepsin gene regulation. Additionally, we extend our understanding of this developing relationship to how such micro-RNAs are being utilized as diagnostic or prognostic tools and highlight their future uses in conjunction with cathepsin gene expression as potential biomarkers within a clinical setting. Full article
(This article belongs to the Special Issue P53 and Hallmarks of Cancer)
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17 pages, 297 KiB  
Review
The Polemic Diagnostic Role of TP53 Mutations in Liquid Biopsies from Breast, Colon and Lung Cancers
by M. Carmen Garrido-Navas, Abel García-Díaz, Maria Pilar Molina-Vallejo, Coral González-Martínez, Miriam Alcaide Lucena, Inés Cañas-García, Clara Bayarri, Juan Ramón Delgado, Encarna González, Jose Antonio Lorente and M. Jose Serrano
Cancers 2020, 12(11), 3343; https://doi.org/10.3390/cancers12113343 - 12 Nov 2020
Cited by 12 | Viewed by 2924
Abstract
Being minimally invasive and thus allowing repeated measures over time, liquid biopsies are taking over traditional solid biopsies in certain circumstances such as those for unreachable tumors, very early stages or treatment monitoring. However, regarding TP53 mutation status analysis, liquid biopsies have not [...] Read more.
Being minimally invasive and thus allowing repeated measures over time, liquid biopsies are taking over traditional solid biopsies in certain circumstances such as those for unreachable tumors, very early stages or treatment monitoring. However, regarding TP53 mutation status analysis, liquid biopsies have not yet substituted tissue samples, mainly due to the lack of concordance between the two types of biopsies. This needs to be examined in a study-dependent manner, taking into account the particular type of liquid biopsy analyzed, that is, circulating tumor cells (CTCs) or cell-free DNA (cfDNA), its involvement in the tumor biology and evolution and, finally, the technology used to analyze each biopsy type. Here, we review the main studies analyzing TP53 mutations in either CTCs or cfDNA in the three more prevalent solid tumors: breast, colon and lung cancers. We evaluate the correlation for mutation status between liquid biopsies and tumor tissue, suggesting possible sources of discrepancies, as well as evaluating the clinical utility of using liquid biopsies for the analysis of TP53 mutation status and the future actions that need to be undertaken to make liquid biopsy analysis a reality for the evaluation of TP53 mutations. Full article
(This article belongs to the Special Issue P53 and Hallmarks of Cancer)
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