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Special Issue "p53 in Cancer and beyond—40 Years after Its Discovery"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2019).

Special Issue Editors

Prof. Dr. Marco M. Candeias
E-Mail Website
Guest Editor
1. Molecular and RNA Cancer Unit, Kyoto University Graduate School of Medicine, Building E Rm 115, Yoshida Konoemachi, Sakyo-ku, Kyoto 606-8501, Japan
2. Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal
3. BioISI — BioSystems & Integrative Sciences, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal
Interests: p53, p53 mRNA, p53 isoforms, mRNA translation; mRNA functions; cancer genetics
Special Issues, Collections and Topics in MDPI journals
Dr. Rieko Ohki
E-Mail
Guest Editor
Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan
Interests: p53; cancer; tumor biology; neuoendocrine tumor; PHLDA3; IER5

Special Issue Information

Dear Colleagues,

The “p53 team” dictates cell fate and sacrifices cell life as demanded, for the greater good of the organism. The p53 team consists of its close family (p53, p63, and p73 genes), a varied number of isoforms, and a plethora of downstream target genes. Together they control cell stemness, division, chromosome integrity, epigenetics, differentiation, senescence and death; response to stress, infection and disease; reproduction, immunity, metabolism, and regeneration. As a consequence, p53 team function is central to our lives, from birth and development to aging and life span in both health and disease.

Forty years after its discovery, we aim to cover important and new aspects of p53 and its team, not only in cancer, but in all the diversity of p53-dependent activities. Authors are invited to review recent work or submit original research in all areas of recent and current p53 research, with an emphasis on work providing molecular insight, including but not limited to novel physiological and pathological functions, or regulatory mechanisms.

We welcome your contributions for this Special Issue on “p53 in Cancer and beyond—40 Years after Its Discovery”.

Dr. Marco M. Candeias
Dr. Rieko Ohki
Guest Editors

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 papers will be 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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.

Published Papers (24 papers)

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Research

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Communication
SLMP53-1 Inhibits Tumor Cell Growth through Regulation of Glucose Metabolism and Angiogenesis in a P53-Dependent Manner
Int. J. Mol. Sci. 2020, 21(2), 596; https://doi.org/10.3390/ijms21020596 - 17 Jan 2020
Cited by 5 | Viewed by 1854
Abstract
The Warburg effect is an emerging hallmark of cancer, which has the tumor suppressor p53 as its major regulator. Herein, we unveiled that p53 activation by (S)-tryptophanol-derived oxazoloisoindolinone (SLMP53-1) mediated the reprograming of glucose metabolism in cancer cells and xenograft human [...] Read more.
The Warburg effect is an emerging hallmark of cancer, which has the tumor suppressor p53 as its major regulator. Herein, we unveiled that p53 activation by (S)-tryptophanol-derived oxazoloisoindolinone (SLMP53-1) mediated the reprograming of glucose metabolism in cancer cells and xenograft human tumor tissue, interfering with angiogenesis and migration. Particularly, we showed that SLMP53-1 regulated glycolysis by downregulating glucose transporter 1 (GLUT1), hexokinase-2 (HK2), and phosphofructokinase-2 isoform 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3 (PFKFB3) (key glycolytic enzymes), while upregulating the mitochondrial markers synthesis of cytochrome c oxidase 2 (SCO2), cytochrome c oxidase subunit 4 (COX4), and OXPHOS mitochondrial complexes. SLMP53-1 also downregulated the monocarboxylate transporter 4 (MCT4), causing the subsequent reduction of lactate export by cancer cells. Besides the acidification of the extracellular environment, SLMP53-1 further increased E-cadherin and reduced metalloproteinase-9 (MMP-9) expression levels in both cancer cells and xenograft human tumor tissue, which suggested the interference of SLMP53-1 in extracellular matrix remodeling and epithelial-to-mesenchymal transition. Consistently, SLMP53-1 depleted angiogenesis, decreasing endothelial cell tube formation and vascular endothelial growth factor (VEGF) expression levels. SLMP53-1 also exhibited synergistic growth inhibitory activity in combination with the metabolic modulator dichloroacetic acid. These data reinforce the promising application of the p53-activating agent SLMP53-1 in cancer therapy, by targeting p53-mediated pathways of growth and dissemination. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Article
The Influence of Quadruplex Structure in Proximity to P53 Target Sequences on the Transactivation Potential of P53 Alpha Isoforms
Int. J. Mol. Sci. 2020, 21(1), 127; https://doi.org/10.3390/ijms21010127 - 24 Dec 2019
Cited by 3 | Viewed by 1395
Abstract
p53 is one of the most studied tumor suppressor proteins that plays an important role in basic biological processes including cell cycle, DNA damage response, apoptosis, and senescence. The human TP53 gene contains alternative promoters that produce N-terminally truncated proteins and can produce [...] Read more.
p53 is one of the most studied tumor suppressor proteins that plays an important role in basic biological processes including cell cycle, DNA damage response, apoptosis, and senescence. The human TP53 gene contains alternative promoters that produce N-terminally truncated proteins and can produce several isoforms due to alternative splicing. p53 function is realized by binding to a specific DNA response element (RE), resulting in the transactivation of target genes. Here, we evaluated the influence of quadruplex DNA structure on the transactivation potential of full-length and N-terminal truncated p53α isoforms in a panel of S. cerevisiae luciferase reporter strains. Our results show that a G-quadruplex prone sequence is not sufficient for transcription activation by p53α isoforms, but the presence of this feature in proximity to a p53 RE leads to a significant reduction of transcriptional activity and changes the dynamics between co-expressed p53α isoforms. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Article
Characterization of p53 Family Homologs in Evolutionary Remote Branches of Holozoa
Int. J. Mol. Sci. 2020, 21(1), 6; https://doi.org/10.3390/ijms21010006 - 18 Dec 2019
Cited by 6 | Viewed by 1547
Abstract
The p53 family of transcription factors plays key roles in development, genome stability, senescence and tumor development, and p53 is the most important tumor suppressor protein in humans. Although intensively investigated for many years, its initial evolutionary history is not yet fully elucidated. [...] Read more.
The p53 family of transcription factors plays key roles in development, genome stability, senescence and tumor development, and p53 is the most important tumor suppressor protein in humans. Although intensively investigated for many years, its initial evolutionary history is not yet fully elucidated. Using bioinformatic and structure prediction methods on current databases containing newly-sequenced genomes and transcriptomes, we present a detailed characterization of p53 family homologs in remote members of the Holozoa group, in the unicellular clades Filasterea, Ichthyosporea and Corallochytrea. Moreover, we show that these newly characterized homologous sequences contain domains that can form structures with high similarity to the human p53 family DNA-binding domain, and some also show similarities to the oligomerization and SAM domains. The presence of these remote homologs demonstrates an ancient origin of the p53 protein family. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Article
The Dual Interactions of p53 with MDM2 and p300: Implications for the Design of MDM2 Inhibitors
Int. J. Mol. Sci. 2019, 20(23), 5996; https://doi.org/10.3390/ijms20235996 - 28 Nov 2019
Cited by 5 | Viewed by 1498
Abstract
Proteins that limit the activity of the tumour suppressor protein p53 are increasingly being targeted for inhibition in a variety of cancers. In addition to the development of small molecules, there has been interest in developing constrained (stapled) peptide inhibitors. A stapled peptide [...] Read more.
Proteins that limit the activity of the tumour suppressor protein p53 are increasingly being targeted for inhibition in a variety of cancers. In addition to the development of small molecules, there has been interest in developing constrained (stapled) peptide inhibitors. A stapled peptide ALRN_6924 that activates p53 by preventing its interaction with its negative regulator Mdm2 has entered clinical trials. This stapled peptide mimics the interaction of p53 with Mdm2. The chances that this peptide could bind to other proteins that may also interact with the Mdm2-binding region of p53 are high; one such protein is the CREB binding protein (CBP)/p300. It has been established that phosphorylated p53 is released from Mdm2 and binds to p300, orchestrating the transcriptional program. We investigate whether molecules such as ALRN_6924 would bind to p300 and, to do so, we used molecular simulations to explore the binding of ATSP_7041, which is an analogue of ALRN_6924. Our study shows that ATSP_7041 preferentially binds to Mdm2 over p300; however, upon phosphorylation, it appears to have a higher affinity for p300. This could result in attenuation of the amount of free p300 available for interacting with p53, and hence reduce its transcriptional efficacy. Our study highlights the importance of assessing off-target effects of peptide inhibitors, particularly guided by the understanding of the networks of protein-protein interactions (PPIs) that are being targeted. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Article
Coordination of miR-192 and miR-22 in p53-Mediated Cell Fate Decision
Int. J. Mol. Sci. 2019, 20(19), 4768; https://doi.org/10.3390/ijms20194768 - 26 Sep 2019
Cited by 7 | Viewed by 1141
Abstract
p53-targeted microRNAs (miRNAs) markedly affect cellular response to DNA damage. These miRNAs may contribute to either cell cycle arrest or apoptosis induction. However, how these miRNAs coordinate to modulate the decision between cell survival and death remains less understood. Here, we developed an [...] Read more.
p53-targeted microRNAs (miRNAs) markedly affect cellular response to DNA damage. These miRNAs may contribute to either cell cycle arrest or apoptosis induction. However, how these miRNAs coordinate to modulate the decision between cell survival and death remains less understood. Here, we developed an integrated model of p53 signaling network to investigate how p53-targeted miR-192 and miR-22 modulate cellular outcome in response to DNA damage. By numerical simulations, we found that p53 is activated progressively depending on the extent of DNA damage. Upon moderate damage, p53 rises to medium levels and induces miR-192 to promote its own activation, facilitating p21 induction and cell cycle arrest. Upon severe damage, p53 reaches high levels and is fully activated due to phosphatase and tensin homolog (PTEN) induction. As a result, it transactivates miR-22 to repress p21 expression and activate E2F1, resulting in apoptosis. Therefore, miR-192 promotes primary activation of p53, while miR-22 promotes apoptosis by downregulating p21. This work may advance the understanding of the mechanism for cell fate decision between life and death by p53-inducible miRNAs. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review

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Review
p53-PHLDA3-Akt Network: The Key Regulators of Neuroendocrine Tumorigenesis
Int. J. Mol. Sci. 2020, 21(11), 4098; https://doi.org/10.3390/ijms21114098 - 08 Jun 2020
Cited by 7 | Viewed by 1347
Abstract
p53 is a well-known tumor suppressor gene and one of the most extensively studied genes in cancer research. p53 functions largely as a transcription factor and can trigger a variety of antiproliferative programs via induction of its target genes. We identified PHLDA3 as [...] Read more.
p53 is a well-known tumor suppressor gene and one of the most extensively studied genes in cancer research. p53 functions largely as a transcription factor and can trigger a variety of antiproliferative programs via induction of its target genes. We identified PHLDA3 as a p53 target gene and found that its protein product is a suppressor of pancreatic neuroendocrine tumors (PanNETs) and a repressor of Akt function. PHLDA3 is frequently inactivated by loss of heterozygosity (LOH) and methylation in human PanNETs, and LOH at the PHLDA3 gene locus correlates with PanNET progression and poor prognosis. In addition, in PHLDA3-deficient mice, pancreatic islet cells proliferate abnormally and acquire resistance to apoptosis. In this article, we briefly review the roles of p53 and Akt in human neuroendocrine tumors (NETs) and describe the relationship between the p53-PHLDA3 and Akt pathways. We also discuss the role of PHLDA3 as a tumor suppressor in various NETs and speculate on the possibility that loss of PHLDA3 function may be a useful prognostic marker for NET patients indicating particular drug therapies. These results suggest that targeting the downstream PHLDA3-Akt pathway might provide new therapies to treat NETs. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review
PHLD Class Proteins: A Family of New Players in the p53 Network
Int. J. Mol. Sci. 2020, 21(10), 3543; https://doi.org/10.3390/ijms21103543 - 17 May 2020
Cited by 2 | Viewed by 915
Abstract
The Pleckstrin Homology-like Domain (PHLD) class of proteins are multifunctional proteins. The class is comprised of two families of proteins, PHLDA and PHLDB, each with 3 members. All members of the families possess a pleckstrin homology (PH) domain. Though identified nearly 30 years [...] Read more.
The Pleckstrin Homology-like Domain (PHLD) class of proteins are multifunctional proteins. The class is comprised of two families of proteins, PHLDA and PHLDB, each with 3 members. All members of the families possess a pleckstrin homology (PH) domain. Though identified nearly 30 years ago, this class of proteins remains understudied with PHLDA family members receiving most of the research attention. Recent studies have also begun to reveal the functions of the PHLDB family proteins in regulation of p53 and AKT signaling pathways important for cancer and metabolism. This review will discuss current research and offer some prospects on the possible roles of both families in cancer and metabolism. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review
P53: A Guardian of Immunity Becomes Its Saboteur through Mutation
Int. J. Mol. Sci. 2020, 21(10), 3452; https://doi.org/10.3390/ijms21103452 - 13 May 2020
Cited by 17 | Viewed by 1944
Abstract
Awareness of the importance of immunity in controlling cancer development triggered research into the impact of its key oncogenic drivers on the immune response, as well as their value as targets for immunotherapy. At the heart of tumour suppression is p53, which was [...] Read more.
Awareness of the importance of immunity in controlling cancer development triggered research into the impact of its key oncogenic drivers on the immune response, as well as their value as targets for immunotherapy. At the heart of tumour suppression is p53, which was discovered in the context of viral infection and now emerges as a significant player in normal and cancer immunity. Wild-type p53 (wt p53) plays fundamental roles in cancer immunity and inflammation. Mutations in p53 not only cripple wt p53 immune functions but also sinisterly subvert the immune function through its neomorphic gain-of-functions (GOFs). The prevalence of mutant p53 across different types of human cancers, which are associated with inflammatory and immune dysfunction, further implicates mutant p53 in modulating cancer immunity, thereby promoting tumorigenesis, metastasis and invasion. In this review, we discuss several mutant p53 immune GOFs in the context of the established roles of wt p53 in regulating and responding to tumour-associated inflammation, and regulating innate and adaptive immunity. We discuss the capacity of mutant p53 to alter the tumour milieu to support immune dysfunction, modulate toll-like receptor (TLR) signalling pathways to disrupt innate immunity and subvert cell-mediated immunity in favour of immune privilege and survival. Furthermore, we expose the potential and challenges associated with mutant p53 as a cancer immunotherapy target and underscore existing therapies that may benefit from inquiry into cancer p53 status. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review
p53-Related Transcription Targets of TAp73 in Cancer Cells—Bona Fide or Distorted Reality?
Int. J. Mol. Sci. 2020, 21(4), 1346; https://doi.org/10.3390/ijms21041346 - 17 Feb 2020
Cited by 7 | Viewed by 1078
Abstract
Identification of p73 as a structural homolog of p53 fueled early studies aimed at determining if it was capable of performing p53-like functions. This led to a conundrum as p73 was discovered to be hardly mutated in cancers, and yet, TAp73, the full-length [...] Read more.
Identification of p73 as a structural homolog of p53 fueled early studies aimed at determining if it was capable of performing p53-like functions. This led to a conundrum as p73 was discovered to be hardly mutated in cancers, and yet, TAp73, the full-length form, was found capable of performing p53-like functions, including transactivation of many p53 target genes in cancer cell lines. Generation of mice lacking p73/TAp73 revealed a plethora of developmental defects, with very limited spontaneous tumors arising only at a later stage. Concurrently, novel TAp73 target genes involved in cellular growth promotion that are not regulated by p53 were identified, mooting the possibility that TAp73 may have diametrically opposite functions to p53 in tumorigenesis. We have therefore comprehensively evaluated the TAp73 target genes identified and validated in human cancer cell lines, to examine their contextual relevance. Data from focused studies aimed at appraising if p53 targets are also regulated by TAp73—often by TAp73 overexpression in cell lines with non-functional p53—were affirmative. However, genome-wide and phenotype-based studies led to the identification of TAp73-regulated genes involved in cellular survival and thus, tumor promotion. Our analyses therefore suggest that TAp73 may not necessarily be p53’s natural substitute in enforcing tumor suppression. It has likely evolved to perform unique functions in regulating developmental processes and promoting cellular growth through entirely different sets of target genes that are not common to, and cannot be substituted by p53. The p53-related targets initially reported to be regulated by TAp73 may therefore represent an experimental possibility rather than the reality. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review
Gain-of-Function Mutations in p53 in Cancer Invasiveness and Metastasis
Int. J. Mol. Sci. 2020, 21(4), 1334; https://doi.org/10.3390/ijms21041334 - 17 Feb 2020
Cited by 11 | Viewed by 1402
Abstract
Forty years of research has proven beyond any doubt that p53 is a key regulator of many aspects of cellular physiology. It is best known for its tumor suppressor function, but it is also a regulator of processes important for maintenance of homeostasis [...] Read more.
Forty years of research has proven beyond any doubt that p53 is a key regulator of many aspects of cellular physiology. It is best known for its tumor suppressor function, but it is also a regulator of processes important for maintenance of homeostasis and stress response. Its activity is generally antiproliferative and when the cell is damaged beyond repair or intensely stressed the p53 protein contributes to apoptosis. Given its key role in preventing cancer it is no wonder that it is the most frequently mutated gene in human cancer. Surprisingly, a subset of missense mutations occurring in p53 (gain-of-function) cause it to lose its suppressor activity and acquire new functionalities that turn the tumor suppressor protein into an oncoprotein. A solid body of evidence exists demonstrating increased malignancy of cancers with mutated p53 in all aspects considered “hallmarks of cancer”. In this review, we summarize current findings concerning the cellular processes altered by gain-of-function mutations in p53 and their influence on cancer invasiveness and metastasis. We also present the variety of molecular mechanisms regulating these processes, including microRNA, direct transcriptional regulation, protein–protein interactions, and more. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
Review
How p53 Molecules Solve the Target DNA Search Problem: A Review
Int. J. Mol. Sci. 2020, 21(3), 1031; https://doi.org/10.3390/ijms21031031 - 04 Feb 2020
Cited by 7 | Viewed by 1441
Abstract
Interactions between DNA and DNA-binding proteins play an important role in many essential cellular processes. A key function of the DNA-binding protein p53 is to search for and bind to target sites incorporated in genomic DNA, which triggers transcriptional regulation. How do p53 [...] Read more.
Interactions between DNA and DNA-binding proteins play an important role in many essential cellular processes. A key function of the DNA-binding protein p53 is to search for and bind to target sites incorporated in genomic DNA, which triggers transcriptional regulation. How do p53 molecules achieve “rapid” and “accurate” target search in living cells? The search dynamics of p53 were expected to include 3D diffusion in solution, 1D diffusion along DNA, and intersegmental transfer between two different DNA strands. Single-molecule fluorescence microscopy enabled the tracking of p53 molecules on DNA and the characterization of these dynamics quantitatively. Recent intensive single-molecule studies of p53 succeeded in revealing each of these search dynamics. Here, we review these studies and discuss the target search mechanisms of p53. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review
P53 and The Immune Response: 40 Years of Exploration—A Plan for the Future
Int. J. Mol. Sci. 2020, 21(2), 541; https://doi.org/10.3390/ijms21020541 - 15 Jan 2020
Cited by 27 | Viewed by 2249
Abstract
The p53 field was born from a marriage of the techniques of cancer virus research and immunology. Over the past 40 years, it has followed the path of cancer research. Now cancer treatments are turning to immunotherapy, and there are many hints of [...] Read more.
The p53 field was born from a marriage of the techniques of cancer virus research and immunology. Over the past 40 years, it has followed the path of cancer research. Now cancer treatments are turning to immunotherapy, and there are many hints of the role of the p53 protein in both the regulation of the innate immune system and as an antigen in adaptive immune responses. The p53 gene and protein are part of the innate immune system, and play an important role in infectious diseases, senescence, aging, and the surveillance of repetitive DNA and RNAs. The mutant form of the p53 protein in cancers elicits both a B-cell antibody response (a tumor antigen) and a CD-8 killer T-cell response (a tumor-specific transplantation antigen). The future will take the p53-immune response field of research into cancer immunotherapy, autoimmunity, inflammatory responses, neuro-degeneration, aging, and life span, and the regulation of epigenetic stability and tissue regeneration. The next 40 years will bring the p53 gene and its proteins out of a cancer focus and into an organismic and environmental focus. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
Review
Regulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway
Int. J. Mol. Sci. 2020, 21(1), 261; https://doi.org/10.3390/ijms21010261 - 30 Dec 2019
Cited by 15 | Viewed by 1937
Abstract
The tumor suppressor p53 and its homologues, p63 and p73, play a pivotal role in the regulation of the DNA damage response, cellular homeostasis, development, aging, and metabolism. A number of mouse studies have shown that a genetic defect in the p53 family [...] Read more.
The tumor suppressor p53 and its homologues, p63 and p73, play a pivotal role in the regulation of the DNA damage response, cellular homeostasis, development, aging, and metabolism. A number of mouse studies have shown that a genetic defect in the p53 family could lead to spontaneous tumor development, embryonic lethality, or severe tissue abnormality, indicating that the activity of the p53 family must be tightly regulated to maintain normal cellular functions. While the p53 family members are regulated at the level of gene expression as well as post-translational modification, they are also controlled at the level of protein stability through the ubiquitin proteasomal pathway. Over the last 20 years, many ubiquitin E3 ligases have been discovered that directly promote protein degradation of p53, p63, and p73 in vitro and in vivo. Here, we provide an overview of such E3 ligases and discuss their roles and functions. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review
How the Other Half Lives: What p53 Does When It Is Not Being a Transcription Factor
Int. J. Mol. Sci. 2020, 21(1), 13; https://doi.org/10.3390/ijms21010013 - 18 Dec 2019
Cited by 19 | Viewed by 2367
Abstract
It has been four decades since the discovery of p53, the designated ‘Guardian of the Genome’. P53 is primarily known as a master transcription factor and critical tumor suppressor, with countless studies detailing the mechanisms by which it regulates a host of gene [...] Read more.
It has been four decades since the discovery of p53, the designated ‘Guardian of the Genome’. P53 is primarily known as a master transcription factor and critical tumor suppressor, with countless studies detailing the mechanisms by which it regulates a host of gene targets and their consequent signaling pathways. However, transcription-independent functions of p53 also strongly define its tumor-suppressive capabilities and recent findings shed light on the molecular mechanisms hinted at by earlier efforts. This review highlights the transcription-independent mechanisms by which p53 influences the cellular response to genomic instability (in the form of replication stress, centrosome homeostasis, and transposition) and cell death. We also pinpoint areas for further investigation in order to better understand the context dependency of p53 transcription-independent functions and how these are perturbed when TP53 is mutated in human cancer. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review
The Emerging Landscape of p53 Isoforms in Physiology, Cancer and Degenerative Diseases
Int. J. Mol. Sci. 2019, 20(24), 6257; https://doi.org/10.3390/ijms20246257 - 11 Dec 2019
Cited by 19 | Viewed by 2189
Abstract
p53, first described four decades ago, is now established as a master regulator of cellular stress response, the “guardian of the genome”. p53 contributes to biological robustness by behaving in a cellular-context dependent manner, influenced by several factors (e.g., cell type, active signalling [...] Read more.
p53, first described four decades ago, is now established as a master regulator of cellular stress response, the “guardian of the genome”. p53 contributes to biological robustness by behaving in a cellular-context dependent manner, influenced by several factors (e.g., cell type, active signalling pathways, the type, extent and intensity of cellular damage, cell cycle stage, nutrient availability, immune function). The p53 isoforms regulate gene transcription and protein expression in response to the stimuli so that the cell response is precisely tuned to the cell signals and cell context. Twelve isoforms of p53 have been described in humans. In this review, we explore the interactions between p53 isoforms and other proteins contributing to their established cellular functions, which can be both tumour-suppressive and oncogenic in nature. Evidence of p53 isoform in human cancers is largely based on RT-qPCR expression studies, usually investigating a particular type of isoform. Beyond p53 isoform functions in cancer, it is implicated in neurodegeneration, embryological development, progeroid phenotype, inflammatory pathology, infections and tissue regeneration, which are described in this review. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review
Do Mutations Turn p53 into an Oncogene?
Int. J. Mol. Sci. 2019, 20(24), 6241; https://doi.org/10.3390/ijms20246241 - 11 Dec 2019
Cited by 29 | Viewed by 2599
Abstract
The key role of p53 as a tumor suppressor became clear when it was realized that this gene is mutated in 50% of human sporadic cancers, and germline mutations expose carriers to cancer risk throughout their lifespan. Mutations in this gene not only [...] Read more.
The key role of p53 as a tumor suppressor became clear when it was realized that this gene is mutated in 50% of human sporadic cancers, and germline mutations expose carriers to cancer risk throughout their lifespan. Mutations in this gene not only abolish the tumor suppressive functions of p53, but also equip the protein with new pro-oncogenic functions. Here, we review the mechanisms by which these new functions gained by p53 mutants promote tumorigenesis. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review
Gain-of-Function Mutant p53: All the Roads Lead to Tumorigenesis
Int. J. Mol. Sci. 2019, 20(24), 6197; https://doi.org/10.3390/ijms20246197 - 08 Dec 2019
Cited by 37 | Viewed by 2851
Abstract
The p53 protein is mutated in about 50% of human cancers. Aside from losing the tumor-suppressive functions of the wild-type form, mutant p53 proteins often acquire inherent, novel oncogenic functions, a phenomenon termed mutant p53 gain-of-function (GOF). A growing body of evidence suggests [...] Read more.
The p53 protein is mutated in about 50% of human cancers. Aside from losing the tumor-suppressive functions of the wild-type form, mutant p53 proteins often acquire inherent, novel oncogenic functions, a phenomenon termed mutant p53 gain-of-function (GOF). A growing body of evidence suggests that these pro-oncogenic functions of mutant p53 proteins are mediated by affecting the transcription of various genes, as well as by protein–protein interactions with transcription factors and other effectors. In the current review, we discuss the various GOF effects of mutant p53, and how it may serve as a central node in a network of genes and proteins, which, altogether, promote the tumorigenic process. Finally, we discuss mechanisms by which “Mother Nature” tries to abrogate the pro-oncogenic functions of mutant p53. Thus, we suggest that targeting mutant p53, via its reactivation to the wild-type form, may serve as a promising therapeutic strategy for many cancers that harbor mutant p53. Not only will this strategy abrogate mutant p53 GOF, but it will also restore WT p53 tumor-suppressive functions. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
Review
The Diverse Functions of Mutant 53, Its Family Members and Isoforms in Cancer
Int. J. Mol. Sci. 2019, 20(24), 6188; https://doi.org/10.3390/ijms20246188 - 07 Dec 2019
Cited by 8 | Viewed by 1436
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review
p53 Isoforms in Cellular Senescence- and Ageing-Associated Biological and Physiological Functions
Int. J. Mol. Sci. 2019, 20(23), 6023; https://doi.org/10.3390/ijms20236023 - 29 Nov 2019
Cited by 15 | Viewed by 1991
Abstract
Cellular senescence, a term originally used to define the characteristics of normal human fibroblasts that reached their replicative limit, is an important factor for ageing, age-related diseases including cancer, and cell reprogramming. These outcomes are mediated by senescence-associated changes in gene expressions, which [...] Read more.
Cellular senescence, a term originally used to define the characteristics of normal human fibroblasts that reached their replicative limit, is an important factor for ageing, age-related diseases including cancer, and cell reprogramming. These outcomes are mediated by senescence-associated changes in gene expressions, which sometimes lead to the secretion of pro-inflammatory factors, or senescence-associated secretory phenotype (SASP) that contribute to paradoxical pro-tumorigenic effects. p53 functions as a transcription factor in cell-autonomous responses such as cell-cycle control, DNA repair, apoptosis, and cellular senescence, and also non-cell-autonomous responses to DNA damage by mediating the SASP function of immune system activation. The human TP53 gene encodes twelve protein isoforms, which provides an explanation for the pleiotropic p53 function on cellular senescence. Recent reports suggest that some short isoforms of p53 may modulate gene expressions in a full-length p53-dependent and -independent manner, in other words, some p53 isoforms cooperate with full-length p53, whereas others operate independently. This review summarizes our current knowledge about the biological activities and functions of p53 isoforms, especially Δ40p53, Δ133p53α, and p53β, on cellular senescence, ageing, age-related disorder, reprogramming, and cancer. Numerous cellular and animal model studies indicate that an unbalance in p53 isoform expression in specific cell types causes age-related disorders such as cancer, premature ageing, and degenerative diseases. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review
The Rich World of p53 DNA Binding Targets: The Role of DNA Structure
Int. J. Mol. Sci. 2019, 20(22), 5605; https://doi.org/10.3390/ijms20225605 - 09 Nov 2019
Cited by 18 | Viewed by 3411
Abstract
The tumor suppressor functions of p53 and its roles in regulating the cell cycle, apoptosis, senescence, and metabolism are accomplished mainly by its interactions with DNA. p53 works as a transcription factor for a significant number of genes. Most p53 target genes contain [...] Read more.
The tumor suppressor functions of p53 and its roles in regulating the cell cycle, apoptosis, senescence, and metabolism are accomplished mainly by its interactions with DNA. p53 works as a transcription factor for a significant number of genes. Most p53 target genes contain so-called p53 response elements in their promoters, consisting of 20 bp long canonical consensus sequences. Compared to other transcription factors, which usually bind to one concrete and clearly defined DNA target, the p53 consensus sequence is not strict, but contains two repeats of a 5′RRRCWWGYYY3′ sequence; therefore it varies remarkably among target genes. Moreover, p53 binds also to DNA fragments that at least partially and often completely lack this consensus sequence. p53 also binds with high affinity to a variety of non-B DNA structures including Holliday junctions, cruciform structures, quadruplex DNA, triplex DNA, DNA loops, bulged DNA, and hemicatenane DNA. In this review, we summarize information of the interactions of p53 with various DNA targets and discuss the functional consequences of the rich world of p53 DNA binding targets for its complex regulatory functions. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review
The Association and Significance of p53 in Gynecologic Cancers: The Potential of Targeted Therapy
Int. J. Mol. Sci. 2019, 20(21), 5482; https://doi.org/10.3390/ijms20215482 - 04 Nov 2019
Cited by 16 | Viewed by 2190
Abstract
Dysfunction of p53 is observed in the many malignant tumors. In cervical cancer, p53 is inactivated by degradation through the complex with human papilloma virus (HPV) oncoprotein E6 and E6-associated protein (E6AP), an E3 ubiquitin protein ligase. In endometrial cancer, overexpression of p53 [...] Read more.
Dysfunction of p53 is observed in the many malignant tumors. In cervical cancer, p53 is inactivated by degradation through the complex with human papilloma virus (HPV) oncoprotein E6 and E6-associated protein (E6AP), an E3 ubiquitin protein ligase. In endometrial cancer, overexpression of p53 in immunohistochemistry is a significant prognostic factor. A discrepancy between p53 overexpression and TP53 mutations is observed in endometrioid endometrial cancer, indicating that the accumulation of p53 protein can be explained by not only gene mutations but also dysregulation of the factors such as ERβ and MDM2. Furthermore, the double-positive expression of immunoreactive estrogen receptor (ER) β and p53 proteins is closely associated with the incidence of metastasis and/or recurrence. High-grade serous ovarian carcinoma (HGSC) arises from secretary cells in the fallopian tube. The secretary cell outgrowth (SCOUT) with TP53 mutations progresses to HGSC via the p53 signature, serous intraepithelial lesion (STIL), and serous intraepithelial carcinoma (STIC), indicating that TP53 mutation is associated with carcinogenesis of HGSC. Clinical application targeting p53 has been approved for some malignant tumors. Gene therapy by the adenovirus-mediated p53 gene transfer system is performed for head and neck cancer. A clinical phase III trial using MDM2/X inhibitors, idasanutlin (RG7388) combined with cytarabine, is being performed involving relapse/refractory acute myeloid leukemia patients. The use of adenoviruses as live vectors which encode wild-type p53 has given promising results in cervical cancer patients. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review
Translational Control in p53 Expression: The Role of 5′-Terminal Region of p53 mRNA
Int. J. Mol. Sci. 2019, 20(21), 5382; https://doi.org/10.3390/ijms20215382 - 29 Oct 2019
Cited by 2 | Viewed by 1361
Abstract
In this review, the latest research concerning the structure and function of the 5′-terminal region of p53 mRNA was discussed. Special attention was focused on defined structural motifs which are present in this region, as well as their conservation and plausible functional role [...] Read more.
In this review, the latest research concerning the structure and function of the 5′-terminal region of p53 mRNA was discussed. Special attention was focused on defined structural motifs which are present in this region, as well as their conservation and plausible functional role in translation. It is known that the length of the 5′-terminal region and the structural environment of initiation codons can strongly modulate translation initiation. The ability of this region of p53 mRNA to bind protein factors was also described with special emphasis on general principles that govern, such RNA-protein interactions. The structural alterations within the 5′-terminal region of p53 mRNA and proteins that bind to this region have a strong impact on the rate of mRNA scanning and on translation efficiency in in vitro assays, in selected cell lines, and under stress conditions. Thus, the structural features of the 5′-terminal region of p53 mRNA seem to be very important for translation and for translation regulation mechanisms. Finally, we suggested topics that, in our opinion, should be further explored for better understanding of the mechanisms of the p53 gene expression regulation at the translational level. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review
Roles of p53 Family Structure and Function in Non-Canonical Response Element Binding and Activation
Int. J. Mol. Sci. 2019, 20(15), 3681; https://doi.org/10.3390/ijms20153681 - 27 Jul 2019
Cited by 8 | Viewed by 1580
Abstract
The p53 canonical consensus sequence is a 10-bp repeat of PuPuPuC(A/T)(A/T)GPyPyPy, separated by a spacer with up to 13 bases. C(A/T)(A/T)G is the core sequence and purine (Pu) and pyrimidine (Py) bases comprise the flanking sequence. However, in the p53 noncanonical sequences, there [...] Read more.
The p53 canonical consensus sequence is a 10-bp repeat of PuPuPuC(A/T)(A/T)GPyPyPy, separated by a spacer with up to 13 bases. C(A/T)(A/T)G is the core sequence and purine (Pu) and pyrimidine (Py) bases comprise the flanking sequence. However, in the p53 noncanonical sequences, there are many variations, such as length of consensus sequence, variance of core sequence or flanking sequence, and variance in number of bases making up the spacer or AT gap composition. In comparison to p53, the p53 family members p63 and p73 have been found to have more tolerance to bind and activate several of these noncanonical sequences. The p53 protein forms monomers, dimers, and tetramers, and its nonspecific binding domain is well-defined; however, those for p63 or p73 are still not fully understood. Study of p63 and p73 structure to determine the monomers, dimers or tetramers to bind and regulate noncanonical sequence is a new challenge which is crucial to obtaining a complete picture of structure and function in order to understand how p63 and p73 regulate genes differently from p53. In this review, we will summarize the rules of p53 family non-canonical sequences, especially focusing on the structure of p53 family members in the regulation of specific target genes. In addition, we will compare different software programs for prediction of p53 family responsive elements containing parameters with canonical or non-canonical sequences. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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Review
Amniotic Fluid Cells, Stem Cells, and p53: Can We Stereotype p53 Functions?
Int. J. Mol. Sci. 2019, 20(9), 2236; https://doi.org/10.3390/ijms20092236 - 07 May 2019
Cited by 3 | Viewed by 2094
Abstract
In recent years, great interest has been devoted to finding alternative sources for human stem cells which can be easily isolated, ideally without raising ethical objections. These stem cells should furthermore have a high proliferation rate and the ability to differentiate into all [...] Read more.
In recent years, great interest has been devoted to finding alternative sources for human stem cells which can be easily isolated, ideally without raising ethical objections. These stem cells should furthermore have a high proliferation rate and the ability to differentiate into all three germ layers. Amniotic fluid, ordinarily discarded as medical waste, is potentially such a novel source of stem cells, and these amniotic fluid derived stem cells are currently gaining a lot of attention. However, further information will be required about the properties of these cells before they can be used for therapeutic purposes. For example, the risk of tumor formation after cell transplantation needs to be explored. The tumor suppressor protein p53, well known for its activity in controlling Cell Prolif.eration and cell death in differentiated cells, has more recently been found to be also active in amniotic fluid stem cells. In this review, we summarize the major findings about human amniotic fluid stem cells since their discovery, followed by a brief overview of the important role played by p53 in embryonic and adult stem cells. In addition, we explore what is known about p53 in amniotic fluid stem cells to date, and emphasize the need to investigate its role, particularly in the context of cell tumorigenicity. Full article
(This article belongs to the Special Issue p53 in Cancer and beyond—40 Years after Its Discovery)
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