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The Functional Landscape of p53

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

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 40808

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Dr. Andreas Prokesch

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Department of Cell Biology, Histology, and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism, and Aging, Medical University of Graz, Graz, Austria
Interests: metabolism; nutrient sensing; fasting; starvation; transcription factor networks
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Dr. Jelena Krstic

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Department of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center for Cell Signaling, Metabolism & Aging, Medical University of Graz, Graz, Austria
Interests: tumor metabolism; tumor heterogeneity; therapy resistance; tumor evolution; metabolic targets and therapies; dietary interventions and cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

On the 20th anniversary marking the publication of the first draft of the Human Genome Project, the journal Nature determined the top 8 'superstar genes' with p53 ranking as unrivalled number one (DOI: 10.1038/d41586-021-00314-6). This is likely owed to the fact that p53 is the most mutated gene in human cancers (>50%) which is reflected in close to 10,000 p53-specific publications since its discovery in 1979. Despite this unparalleled wealth of information, novel roles of p53 are continuously being reported. Thus, the canonical p53-regulated processes – that is cell-cycle inhibition, apoptosis, and DNA-damage response - are constantly extended to a vast functional spectrum that includes, but is not limited to, metabolic and immune regulation, stem cell biology, ferroptosis, and autophagy. Mechanistically, p53 acts as a transcription factor, coordinating expression of downstream target programs in a context-specific manner, but also steers cellular responses through protein-protein interaction networks. This functional diversity places p53 square in the centre of various physiological and pathological processes way beyond tumor suppression. In this special issue, we want to solicit research and review articles, exemplary of the broad functional landscape of p53. We welcome submissions that pinpoint cutting-edge questions in the area of p53 biology, including the regulation of p53 activity, context-specific p53 signaling and/or novel roles of p53 in health and disease. Results coming from (multi)-omics approaches are particularly encouraged.

Dr. Andreas Prokesch
Dr. Jelena Krstic
Guest Editors

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Keywords

p53
cell death
cell cycle
stem cells
metabolism
immune regulation
autophagy
cancer

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17 pages, 4261 KiB

Open AccessArticle

A Quantitative Systems Approach to Define Novel Effects of Tumour p53 Mutations on Binding Oncoprotein MDM2

by Manuel Fuentes, Sanjeeva Srivastava, Angela M. Gronenborn and Joshua LaBaer

Int. J. Mol. Sci. 2022, 23(1), 53; https://doi.org/10.3390/ijms23010053 - 21 Dec 2021

Cited by 1 | Viewed by 2772

Abstract

Understanding transient protein interactions biochemically at the proteome scale remains a long-standing challenge. Current tools developed to study protein interactions in high-throughput measure stable protein complexes and provide binary readouts; they do not elucidate dynamic and weak protein interactions in a proteome. The majority of protein interactions are transient and cover a wide range of affinities. Nucleic acid programmable protein arrays (NAPPA) are self-assembling protein microarrays produced by freshly translating full-length proteins in situ on the array surface. Herein, we have coupled NAPPA to surface plasmon resonance imaging (SPRi) to produce a novel label-free platform that measures many protein interactions in real-time allowing the determination of the KDs and rate constants. The developed novel NAPPA-SPRi technique showed excellent ability to study protein-protein interactions of clinical mutants of p53 with its regulator MDM2. Furthermore, this method was employed to identify mutant p53 proteins insensitive to the drug nutlin-3, currently in clinical practice, which usually disrupts the p53-MDM2 interactions. Thus, significant differences in the interactions were observed for p53 mutants on the DNA binding domain (Arg-273-Cys, Arg-273-His, Arg-248-Glu, Arg-280-Lys), on the structural domain (His-179-Tyr, Cys-176-Phe), on hydrophobic moieties in the DNA binding domain (Arg-280-Thr, Pro-151-Ser, Cys-176-Phe) and hot spot mutants (Gly-245-Cys, Arg-273-Leu, Arg-248-Glu, Arg-248-Gly), which signifies the importance of point mutations on the MDM2 interaction and nutlin3 effect, even in molecular locations related to other protein activities. Full article

(This article belongs to the Special Issue The Functional Landscape of p53)

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17 pages, 2117 KiB

Open AccessArticle

p53 Transactivation Domain Mediates Binding and Phase Separation with Poly-PR/GR

by Sinem Usluer, Emil Spreitzer, Benjamin Bourgeois and Tobias Madl

Int. J. Mol. Sci. 2021, 22(21), 11431; https://doi.org/10.3390/ijms222111431 - 22 Oct 2021

Cited by 11 | Viewed by 3355

Abstract

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the presence of poly-PR/GR dipeptide repeats, which are encoded by the chromosome 9 open reading frame 72 (C9orf72) gene. Recently, it was shown that poly-PR/GR alters chromatin accessibility, which results in the stabilization and enhancement of transcriptional activity of the tumor suppressor p53 in several neurodegenerative disease models. A reduction in p53 protein levels protects against poly-PR and partially against poly-GR neurotoxicity in cells. Moreover, in model organisms, a reduction of p53 protein levels protects against neurotoxicity of poly-PR. Here, we aimed to study the detailed molecular mechanisms of how p53 contributes to poly-PR/GR-mediated neurodegeneration. Using a combination of biophysical techniques such as nuclear magnetic resonance (NMR) spectroscopy, fluorescence polarization, turbidity assays, and differential interference contrast (DIC) microscopy, we found that p53 physically interacts with poly-PR/GR and triggers liquid–liquid phase separation of p53. We identified the p53 transactivation domain 2 (TAD2) as the main binding site for PR25/GR25 and showed that binding of poly-PR/GR to p53 is mediated by a network of electrostatic and/or hydrophobic interactions. Our findings might help to understand the mechanistic role of p53 in poly-PR/GR-associated neurodegeneration. Full article

(This article belongs to the Special Issue The Functional Landscape of p53)

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25 pages, 36012 KiB

Open AccessArticle

Transcriptome Analysis of Cells Exposed to Actinomycin D and Nutlin-3a Reveals New Candidate p53-Target Genes and Indicates That CHIR-98014 Is an Important Inhibitor of p53 Activity

by Barbara Łasut-Szyszka, Beata Małachowska, Agnieszka Gdowicz-Kłosok, Małgorzata Krześniak, Magdalena Głowala-Kosińska, Artur Zajkowicz and Marek Rusin

Int. J. Mol. Sci. 2021, 22(20), 11072; https://doi.org/10.3390/ijms222011072 - 14 Oct 2021

Cited by 6 | Viewed by 3253

Abstract

Co-treatment with actinomycin D and nutlin-3a (A + N) strongly activates p53. Previously we reported that CHIR-98014 (GSK-3 kinase inhibitor), acting in cells exposed to A + N, prevents activation of TREM2-an innate immunity and p53-regulated gene associated with Alzheimer’s disease. In order to find novel candidate p53-target genes and genes regulated by CHIR-98014, we performed RNA-Seq of control A549 cells and the cells exposed to A + N, A + N with CHIR-98014 or to CHIR-98014. We validated the data for selected genes using RT-PCR and/or Western blotting. Using CRISPR/Cas9 technology we generated p53-deficient cells. These tools enabled us to identify dozens of candidate p53-regulated genes. We confirmed that p53 participates in upregulation of BLNK, APOE and IRF1. BLNK assists in activation of immune cells, APOE codes for apolipoprotein associated with Alzheimer’s disease and IRF1 is activated by interferon gamma and regulates expression of antiviral genes. CHIR-98014 prevented or inhibited the upregulation of a fraction of genes stimulated by A + N. Downregulation of GSK-3 did not mimic the activity of CHIR-98014. Our data generate the hypothesis, that an unidentified kinase inhibited by CHIR-98014, participates in modification of p53 and enables it to activate a subset of its target genes, e.g., the ones associated with innate immunity. Full article

(This article belongs to the Special Issue The Functional Landscape of p53)

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18 pages, 5874 KiB

Open AccessArticle

Differential Transcriptional Regulation of Polymorphic p53 Codon 72 in Metabolic Pathways

by Bu-Yeo Kim, Seo-Young Lee and Sun-Ku Chung

Int. J. Mol. Sci. 2021, 22(19), 10793; https://doi.org/10.3390/ijms221910793 - 6 Oct 2021

Cited by 3 | Viewed by 2078

Abstract

p53 is a transcription factor that is activated under DNA damage stress and regulates the expression of proapoptotic genes including the expression of growth arrest genes to subsequently determine the fate of cells. To investigate the functional differences of polymorphic p53 codon 72, we constructed isogenic lines encoding each polymorphic p53 codon 72 based on induced pluripotent stem cells, which can endogenously express each polymorphic p53 protein only, encoding either the arginine 72 (R72) variant or proline 72 (P72) variant, respectively. We found that there was no significant functional difference between P72 and R72 cells in growth arrest or apoptosis as a representative function of p53. In the comprehensive analysis, the expression pattern of the common p53 target genes, including cell cycle arrest or apoptosis, was also increased regardless of the polymorphic p53 codon 72 status, whereas the expression pattern involved in metabolism was decreased and more significant in R72 than in P72 cells. This study noted that polymorphic p53 codon 72 differentially regulated the functional categories of metabolism and not the pathways that determine cell fate, such as growth arrest and apoptosis in cells exposed to genotoxic stress. Full article

(This article belongs to the Special Issue The Functional Landscape of p53)

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14 pages, 3157 KiB

Open AccessArticle

Cytosolic 5′-Nucleotidase II Silencing in Lung Tumor Cells Regulates Metabolism through Activation of the p53/AMPK Signaling Pathway

by Rossana Pesi, Simone Allegrini, Mercedes Garcia-Gil, Lucia Piazza, Roberta Moschini, Lars Petter Jordheim, Marcella Camici and Maria Grazia Tozzi

Int. J. Mol. Sci. 2021, 22(13), 7004; https://doi.org/10.3390/ijms22137004 - 29 Jun 2021

Cited by 4 | Viewed by 2634

Abstract

Cytosolic 5′-nucleotidase II (cN-II) is an allosteric catabolic enzyme that hydrolyzes IMP, GMP, and AMP. The enzyme can assume at least two different structures, being the more active conformation stabilized by ATP and the less active by inorganic phosphate. Therefore, the variation in ATP concentration can control both structure and activity of cN-II. In this paper, using a capillary electrophoresis technique, we demonstrated that a partial silencing of cN-II in a pulmonary carcinoma cell line (NCI-H292) is accompanied by a decrease in adenylate pool, without affecting the energy charge. We also found that cN-II silencing decreased proliferation and increased oxidative metabolism, as indicated by the decreased production of lactate. These effects, as demonstrated by Western blotting, appear to be mediated by both p53 and AMP-activated protein kinase, as most of them are prevented by pifithrin-α, a known p53 inhibitor. These results are in line with our previous observations of a shift towards a more oxidative and less proliferative phenotype of tumoral cells with a low expression of cN-II, thus supporting the search for specific inhibitors of this enzyme as a therapeutic tool for the treatment of tumors. Full article

(This article belongs to the Special Issue The Functional Landscape of p53)

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Review

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23 pages, 969 KiB

Open AccessReview

Regulation of p53 and Cancer Signaling by Heat Shock Protein 40/J-Domain Protein Family Members

by Atsushi Kaida and Tomoo Iwakuma

Int. J. Mol. Sci. 2021, 22(24), 13527; https://doi.org/10.3390/ijms222413527 - 16 Dec 2021

Cited by 13 | Viewed by 4926

Abstract

Heat shock proteins (HSPs) are molecular chaperones that assist diverse cellular activities including protein folding, intracellular transportation, assembly or disassembly of protein complexes, and stabilization or degradation of misfolded or aggregated proteins. HSP40, also known as J-domain proteins (JDPs), is the largest family with over fifty members and contains highly conserved J domains responsible for binding to HSP70 and stimulation of the ATPase activity as a co-chaperone. Tumor suppressor p53 (p53), the most frequently mutated gene in human cancers, is one of the proteins that functionally interact with HSP40/JDPs. The majority of p53 mutations are missense mutations, resulting in acquirement of unexpected oncogenic activities, referred to as gain of function (GOF), in addition to loss of the tumor suppressive function. Moreover, stability and levels of wild-type p53 (wtp53) and mutant p53 (mutp53) are crucial for their tumor suppressive and oncogenic activities, respectively. However, the regulatory mechanisms of wtp53 and mutp53 are not fully understood. Accumulating reports demonstrate regulation of wtp53 and mutp53 levels and/or activities by HSP40/JDPs. Here, we summarize updated knowledge related to the link of HSP40/JDPs with p53 and cancer signaling to improve our understanding of the regulation of tumor suppressive wtp53 and oncogenic mutp53 GOF activities. Full article

(This article belongs to the Special Issue The Functional Landscape of p53)

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16 pages, 1594 KiB

Open AccessReview

Differential p53-Mediated Cellular Responses to DNA-Damaging Therapeutic Agents

by Lindsey Carlsen and Wafik S. El-Deiry

Int. J. Mol. Sci. 2021, 22(21), 11828; https://doi.org/10.3390/ijms222111828 - 31 Oct 2021

Cited by 22 | Viewed by 3637

Abstract

The gene TP53, which encodes the tumor suppressor protein p53, is mutated in about 50% of cancers. In response to cell stressors like DNA damage and after treatment with DNA-damaging therapeutic agents, p53 acts as a transcription factor to activate subsets of target genes which carry out cell fates such as apoptosis, cell cycle arrest, and DNA repair. Target gene selection by p53 is controlled by a complex regulatory network whose response varies across contexts including treatment type, cell type, and tissue type. The molecular basis of target selection across these contexts is not well understood. Knowledge gained from examining p53 regulatory network profiles across different DNA-damaging agents in different cell types and tissue types may inform logical ways to optimally manipulate the network to encourage p53-mediated tumor suppression and anti-tumor immunity in cancer patients. This may be achieved with combination therapies or with p53-reactivating targeted therapies. Here, we review the basics of the p53 regulatory network in the context of differential responses to DNA-damaging agents; discuss recent efforts to characterize differential p53 responses across treatment types, cell types, and tissue types; and examine the relevance of evaluating these responses in the tumor microenvironment. Finally, we address open questions including the potential relevance of alternative p53 transcriptional functions, p53 transcription-independent functions, and p53-independent functions in the response to DNA-damaging therapeutics. Full article

(This article belongs to the Special Issue The Functional Landscape of p53)

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19 pages, 1922 KiB

Open AccessReview

At a Crossroads to Cancer: How p53-Induced Cell Fate Decisions Secure Genome Integrity

by Dario Rizzotto, Lukas Englmaier and Andreas Villunger

Int. J. Mol. Sci. 2021, 22(19), 10883; https://doi.org/10.3390/ijms221910883 - 8 Oct 2021

Cited by 44 | Viewed by 8355

Abstract

P53 is known as the most critical tumor suppressor and is often referred to as the guardian of our genome. More than 40 years after its discovery, we are still struggling to understand all molecular details on how this transcription factor prevents oncogenesis or how to leverage current knowledge about its function to improve cancer treatment. Multiple cues, including DNA-damage or mitotic errors, can lead to the stabilization and nuclear translocation of p53, initiating the expression of multiple target genes. These transcriptional programs may be cell-type- and stimulus-specific, as is their outcome that ultimately imposes a barrier to cellular transformation. Cell cycle arrest and cell death are two well-studied consequences of p53 activation, but, while being considered critical, they do not fully explain the consequences of p53 loss-of-function phenotypes in cancer. Here, we discuss how mitotic errors alert the p53 network and give an overview of multiple ways that p53 can trigger cell death. We argue that a comparative analysis of different types of p53 responses, elicited by different triggers in a time-resolved manner in well-defined model systems, is critical to understand the cell-type-specific cell fate induced by p53 upon its activation in order to resolve the remaining mystery of its tumor-suppressive function. Full article

(This article belongs to the Special Issue The Functional Landscape of p53)

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25 pages, 3259 KiB

Open AccessReview

Mathematical Modelling of p53 Signalling during DNA Damage Response: A Survey

by Ján Eliaš and Cicely K. Macnamara

Int. J. Mol. Sci. 2021, 22(19), 10590; https://doi.org/10.3390/ijms221910590 - 30 Sep 2021

Cited by 12 | Viewed by 3776

Abstract

No gene has garnered more interest than p53 since its discovery over 40 years ago. In the last two decades, thanks to seminal work from Uri Alon and Ghalit Lahav, p53 has defined a truly synergistic topic in the field of mathematical biology, with a rich body of research connecting mathematic endeavour with experimental design and data. In this review we survey and distill the extensive literature of mathematical models of p53. Specifically, we focus on models which seek to reproduce the oscillatory dynamics of p53 in response to DNA damage. We review the standard modelling approaches used in the field categorising them into three types: time delay models, spatial models and coupled negative-positive feedback models, providing sample model equations and simulation results which show clear oscillatory dynamics. We discuss the interplay between mathematics and biology and show how one informs the other; the deep connections between the two disciplines has helped to develop our understanding of this complex gene and paint a picture of its dynamical response. Although yet more is to be elucidated, we offer the current state-of-the-art understanding of p53 response to DNA damage. Full article

(This article belongs to the Special Issue The Functional Landscape of p53)

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17 pages, 3259 KiB

Open AccessReview

p53 Activation in Genetic Disorders: Different Routes to the Same Destination

by Yu-Young Tsai, Chun-Hao Su and Woan-Yuh Tarn

Int. J. Mol. Sci. 2021, 22(17), 9307; https://doi.org/10.3390/ijms22179307 - 27 Aug 2021

Cited by 10 | Viewed by 4441

Abstract

The tumor suppressor p53 is critical for preventing neoplastic transformation and tumor progression. Inappropriate activation of p53, however, has been observed in a number of human inherited disorders that most often affect development of the brain, craniofacial region, limb skeleton, and hematopoietic system. Genes related to these developmental disorders are essentially involved in transcriptional regulation/chromatin remodeling, rRNA metabolism, DNA damage-repair pathways, telomere maintenance, and centrosome biogenesis. Perturbation of these activities or cellular processes may result in p53 accumulation in cell cultures, animal models, and perhaps humans as well. Mouse models of several p53 activation-associated disorders essentially recapitulate human traits, and inactivation of p53 in these models can alleviate disorder-related phenotypes. In the present review, we focus on how dysfunction of the aforementioned biological processes causes developmental defects via excessive p53 activation. Notably, several disease-related genes exert a pleiotropic effect on those cellular processes, which may modulate the magnitude of p53 activation and establish or disrupt regulatory loops. Finally, we discuss potential therapeutic strategies for genetic disorders associated with p53 misactivation. Full article

(This article belongs to the Special Issue The Functional Landscape of p53)

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