Special Issue "Recent Advances in p53"

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Natural and Bio-inspired Molecules".

Deadline for manuscript submissions: closed (31 May 2020).

Special Issue Editor

Dr. Gabriella D’Orazi
E-Mail Website
Guest Editor
Department of Research, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
Interests: tumor biology; p53; HIPK2; molecular oncology; apoptosis; autophagy; resistance to therapies; solid tumors
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is about p53, one of the most intensively studied tumor suppressor proteins that, in some circumstances, can acquire oncogenic function. Since its discovery, many cellular functions have been ascribed to p53, such as transcription regulation and signalling to apoptosis, involvement in the response to stress, senescence, DNA repair, metabolism, immunity, epigenetic regulation. Perturbation of p53 signalling pathways is required for the development of most cancers, and studies about the restoration or reactivation of p53 function have recently showed significant therapeutic benefit. Over half of all human cancers demonstrate alterations in p53 that not only attenuate or eliminate its tumor suppressor function but also can result in the gain of a novel transforming function, contributing to cancer progression. Much knowledge still needs to be acquired about the multiple facets of this intriguing protein. Here, we welcome papers describing recent advances in understanding p53 function and dysfunction, with an emphasis on novel molecules targeting p53 reactivation for translational purposes.

Prof. Gabriella D’Orazi
Guest Editor

Manuscript Submission Information

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Keywords

  • p53
  • Small molecules
  • Tumor suppressor
  • Apoptosis
  • Tumor–host interaction
  • Targeted therapies
  • Tumor microenvironment (TME)

Published Papers (14 papers)

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Editorial

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Editorial
Recent Advances in p53
Biomolecules 2021, 11(2), 211; https://doi.org/10.3390/biom11020211 - 03 Feb 2021
Viewed by 482
Abstract
Tumor suppressor protein p53 (TP53) is a key transcription factor that, in response to various stress signals, regulates numerous genes involved in a broad range of cellular functions including DNA repair, apoptosis, cell cycle arrest, senescence, metabolism, etc [...] Full article
(This article belongs to the Special Issue Recent Advances in p53)

Research

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Article
The Mutant p53-Driven Secretome Has Oncogenic Functions in Pancreatic Ductal Adenocarcinoma Cells
Biomolecules 2020, 10(6), 884; https://doi.org/10.3390/biom10060884 - 09 Jun 2020
Cited by 5 | Viewed by 953
Abstract
The cancer secretome is a rich repository of useful information for both cancer biology and clinical oncology. A better understanding of cancer secretome is particularly relevant for pancreatic ductal adenocarcinoma (PDAC), whose extremely high mortality rate is mainly due to early metastasis, resistance [...] Read more.
The cancer secretome is a rich repository of useful information for both cancer biology and clinical oncology. A better understanding of cancer secretome is particularly relevant for pancreatic ductal adenocarcinoma (PDAC), whose extremely high mortality rate is mainly due to early metastasis, resistance to conventional treatments, lack of recognizable symptoms, and assays for early detection. TP53 gene is a master transcriptional regulator controlling several key cellular pathways and it is mutated in ~75% of PDACs. We report the functional effect of the hot-spot p53 mutant isoforms R175H and R273H on cancer cell secretome, showing their influence on proliferation, chemoresistance, apoptosis, and autophagy, as well as cell migration and epithelial-mesenchymal transition. We compared the secretome of p53-null AsPC-1 PDAC cells after ectopic over-expression of R175H-mutp53 or R273H-mutp53 to identify the differentially secreted proteins by mutant p53. By using high-resolution SWATH-MS technology, we found a great number of differentially secreted proteins by the two p53 mutants, 15 of which are common to both mutants. Most of these secreted proteins are reported to promote cancer progression and epithelial-mesenchymal transition and might constitute a biomarker secreted signature that is driven by the hot-spot p53 mutants in PDAC. Full article
(This article belongs to the Special Issue Recent Advances in p53)
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Article
PBA Preferentially Impairs Cell Survival of Glioblastomas Carrying mutp53 by Reducing Its Expression Level, Stabilizing wtp53, Downregulating the Mevalonate Kinase and Dysregulating UPR
Biomolecules 2020, 10(4), 586; https://doi.org/10.3390/biom10040586 - 10 Apr 2020
Cited by 3 | Viewed by 779
Abstract
Phenylbutyrate (PBA) is a derivative of Butyric Acid (BA), which has the characteristics of being a histone deacetylase (HDAC) inhibitor and acting as a chemical chaperone. It has the potential to counteract a variety of different diseases, from neurodegeneration to cancer. In this [...] Read more.
Phenylbutyrate (PBA) is a derivative of Butyric Acid (BA), which has the characteristics of being a histone deacetylase (HDAC) inhibitor and acting as a chemical chaperone. It has the potential to counteract a variety of different diseases, from neurodegeneration to cancer. In this study, we investigated the cytotoxic effect of PBA against glioblastoma cells carrying wt or mutant (mut) p53 and found that it exerted a higher cytotoxic effect against the latter in comparison with the former. This could be due to the downregulation of mutp53, to whose pro-survival effects cancer cells become addicted. In correlation with mutp53 reduction and wtp53 activation, PBA downregulated the expression level of mevalonate kinase (MVK), a key kinase of the mevalonate pathway strongly involved in cancer cell survival. Here we differentiated the chaperoning function of PBA from the others anti-cancer potentiality by comparing its effects to those exerted by NaB, another HDACi that derives from BA but, lacking the phenyl group, cannot act as a chemical chaperone. Interestingly, we observed that PBA induced a stronger cytotoxic effect compared to NaB against U373 cells as it skewed the Unfolded Protein Response (UPR) towards cell death induction, upregulating CHOP and downregulating BIP, and was more efficient in downregulating MVK. The findings of this study suggest that PBA represents a promising molecule against glioblastomas, especially those carrying mutp53, and its use, approved by FDA for urea cycle disorders, should be extended to the glioblastoma anticancer therapy. Full article
(This article belongs to the Special Issue Recent Advances in p53)
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Article
A Protein in the Yeast Saccharomyces cerevisiae Presents DNA Binding Homology to the p53 Checkpoint Protein and Tumor Suppressor
Biomolecules 2020, 10(3), 417; https://doi.org/10.3390/biom10030417 - 07 Mar 2020
Cited by 2 | Viewed by 1125
Abstract
Saccharomyces cerevisiae does not contain a p53 homolog. Utilizing this yeast as an in vivo test tube model, our aim was to investigate if a yeast protein would show p53 DNA binding homology. Electrophoretic mobility shift analyses revealed the formation of specific DNA-protein [...] Read more.
Saccharomyces cerevisiae does not contain a p53 homolog. Utilizing this yeast as an in vivo test tube model, our aim was to investigate if a yeast protein would show p53 DNA binding homology. Electrophoretic mobility shift analyses revealed the formation of specific DNA-protein complexes consisting of S. cerevisiae nuclear protein(s) and oligonucleotides containing p53 DNA binding sites. A S. cerevisiae p53 binding site factor (Scp53BSF) bound to a p53 synthetic DNA-consensus sequence (SCS) and a p53 binding-site sequence from the MDM2 oncogene. The complexes were of comparable size. Like mammalian p53, the affinity of Scp53BSF for the SCS oligonucleotide was higher than for the MDM2 oligonucleotide. Binding of Scp53BSF to the SCS and MDM2 oligonucleotides was strongly competed by unlabeled oligonucleotides containing mammalian p53 sites, but very little by a mutated site oligonucleotide. Importantly, Scp53BSF-DNA binding activity was significantly induced in extracts from cells with DNA damage. This resulted in dose-dependent coordinated activation of transcription when using p53-binding site reporter constructs. An ancient p53-like DNA binding protein may have been found, and activation of DNA-associated factors to p53 response elements may have functions not yet determined. Full article
(This article belongs to the Special Issue Recent Advances in p53)
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Article
TP53 Mutations in Serum Circulating Cell-Free Tumor DNA As Longitudinal Biomarker for High-Grade Serous Ovarian Cancer
Biomolecules 2020, 10(3), 415; https://doi.org/10.3390/biom10030415 - 07 Mar 2020
Cited by 5 | Viewed by 1047
Abstract
The aim of this study was to determine an optimal workflow to detect TP53 mutations in baseline and longitudinal serum cell free DNA (cfDNA) from high-grade serous ovarian carcinomas (HGSOC) patients and to define whether TP53 mutations are suitable as biomarker for disease. [...] Read more.
The aim of this study was to determine an optimal workflow to detect TP53 mutations in baseline and longitudinal serum cell free DNA (cfDNA) from high-grade serous ovarian carcinomas (HGSOC) patients and to define whether TP53 mutations are suitable as biomarker for disease. TP53 was investigated in tissue and archived serum from 20 HGSOC patients by a next-generation sequencing (NGS) workflow alone or combined with digital PCR (dPCR). AmpliSeq™-focused NGS panels and customized dPCR assays were used for tissue DNA and longitudinal cfDNAs, and Oncomine NGS panel with molecular barcoding was used for baseline cfDNAs. TP53 missense mutations were observed in 17 tissue specimens and in baseline cfDNA for 4/8 patients by AmpliSeq, 6/9 patients by Oncomine, and 4/6 patients by dPCR. Mutations in cfDNA were detected in 4/6 patients with residual disease and 3/4 patients with disease progression within six months, compared to 5/11 patients with no residual disease and 6/13 patients with progression after six months. Finally, mutations were detected at progression in 5/6 patients, but not during chemotherapy. NGS with molecular barcoding and dPCR were most optimal workflows to detect TP53 mutations in baseline and longitudinal serum cfDNA, respectively. TP53 mutations were undetectable in cfDNA during treatment but re-appeared at disease progression, illustrating its promise as a biomarker for disease monitoring. Full article
(This article belongs to the Special Issue Recent Advances in p53)
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Article
Interplay between Endoplasmic Reticulum (ER) Stress and Autophagy Induces Mutant p53H273 Degradation
Biomolecules 2020, 10(3), 392; https://doi.org/10.3390/biom10030392 - 03 Mar 2020
Cited by 6 | Viewed by 1086
Abstract
The unfolded protein response (UPR) is an adaptive response to intrinsic and external stressors, and it is mainly activated by the accumulation of misfolded proteins at the endoplasmic reticulum (ER) lumen producing ER stress. The UPR signaling network is interconnected with autophagy, the [...] Read more.
The unfolded protein response (UPR) is an adaptive response to intrinsic and external stressors, and it is mainly activated by the accumulation of misfolded proteins at the endoplasmic reticulum (ER) lumen producing ER stress. The UPR signaling network is interconnected with autophagy, the proteolytic machinery specifically devoted to clearing misfolded proteins in order to survive bioenergetic stress and/or induce cell death. Oncosuppressor TP53 may undergo inactivation following missense mutations within the DNA-binding domain (DBD), and mutant p53 (mutp53) proteins may acquire a misfolded conformation, often due to the loss of the DBD-bound zinc ion, leading to accumulation of hyperstable mutp53 proteins that correlates with more aggressive tumors, resistance to therapies, and poorer outcomes. We previously showed that zinc supplementation induces mutp53 protein degradation by autophagy. Here, we show that mutp53 (i.e., Arg273) degradation following zinc supplementation is correlated with activation of ER stress and of the IRE1α/XBPI arm of the UPR. ER stress inhibition with chemical chaperone 4-phenyl butyrate (PBA) impaired mutp53 downregulation, which is similar to IRE1α/XBPI specific inhibition, reducing cancer cell death. Knockdown of mutp53 failed to induce UPR/autophagy activation indicating that the effect of zinc on mutp53 folding was likely the key event occurring in ER stress activation. Recently discovered small molecules targeting components of the UPR show promise as a novel anticancer therapeutic intervention. However, our findings showing UPR activation during mutp53 degradation indicate that caution is necessary in the design of therapies that inhibit UPR components. Full article
(This article belongs to the Special Issue Recent Advances in p53)
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Article
Investigation of a Direct Interaction between miR4749 and the Tumor Suppressor p53 by Fluorescence, FRET and Molecular Modeling
Biomolecules 2020, 10(2), 346; https://doi.org/10.3390/biom10020346 - 22 Feb 2020
Cited by 2 | Viewed by 952
Abstract
The interactions between the DNA binding domain (DBD) of the tumor suppressor p53 and miR4749, characterized by a high sequence similarity with the DNA Response Element (RE) of p53, was investigated by fluorescence spectroscopy combined with computational modeling and docking. Fluorescence quenching experiments [...] Read more.
The interactions between the DNA binding domain (DBD) of the tumor suppressor p53 and miR4749, characterized by a high sequence similarity with the DNA Response Element (RE) of p53, was investigated by fluorescence spectroscopy combined with computational modeling and docking. Fluorescence quenching experiments witnessed the formation of a specific complex between DBD and miR4749 with an affinity of about 105 M. Förster Resonance Energy Transfer (FRET) allowed us to measure a distance of 3.9 ± 0.3 nm, between the lone tryptophan of DBD and an acceptor dye suitably bound to miR4749. Such information, combined with a computational modeling approach, allowed us to predict possible structures for the DBD-miR4749 complex. A successive docking refinement, complemented with binding free energy calculations, led us to single out a best model for the DBD-miR4749 complex. We found that the interaction of miR4749 involves the DBD L3 loop and the H1 helix, close to the Zn-finger motif; with this suggesting that miR4749 could directly inhibit the p53 interaction with DNA. These results might inspire new therapeutic strategies finalized to restore the p53 functional activity. Full article
(This article belongs to the Special Issue Recent Advances in p53)
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Review

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Review
Recent Synthetic Approaches towards Small Molecule Reactivators of p53
Biomolecules 2020, 10(4), 635; https://doi.org/10.3390/biom10040635 - 20 Apr 2020
Cited by 7 | Viewed by 1579
Abstract
The tumor suppressor protein p53 is often called “the genome guardian” and controls the cell cycle and the integrity of DNA, as well as other important cellular functions. Its main function is to trigger the process of apoptosis in tumor cells, and approximately [...] Read more.
The tumor suppressor protein p53 is often called “the genome guardian” and controls the cell cycle and the integrity of DNA, as well as other important cellular functions. Its main function is to trigger the process of apoptosis in tumor cells, and approximately 50% of all cancers are related to the inactivation of the p53 protein through mutations in the TP53 gene. Due to the association of mutant p53 with cancer therapy resistance, different forms of restoration of p53 have been subject of intense research in recent years. In this sense, this review focus on the main currently adopted approaches for activation and reactivation of p53 tumor suppressor function, focusing on the synthetic approaches that are involved in the development and preparation of such small molecules. Full article
(This article belongs to the Special Issue Recent Advances in p53)
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Review
The Status of p53 Oligomeric and Aggregation States in Cancer
Biomolecules 2020, 10(4), 548; https://doi.org/10.3390/biom10040548 - 04 Apr 2020
Cited by 10 | Viewed by 1671
Abstract
Despite being referred to as the guardian of the genome, when impacted by mutations, p53 can lose its protective functions and become a renegade. The malignant transformation of p53 occurs on multiple levels, such as altered DNA binding properties, acquisition of novel cellular [...] Read more.
Despite being referred to as the guardian of the genome, when impacted by mutations, p53 can lose its protective functions and become a renegade. The malignant transformation of p53 occurs on multiple levels, such as altered DNA binding properties, acquisition of novel cellular partners, or associating into different oligomeric states. The consequences of these transformations can be catastrophic. Ongoing studies have implicated different oligomeric p53 species as having a central role in cancer biology; however, the correlation between p53 oligomerization status and oncogenic activities in cancer progression remains an open conundrum. In this review, we summarize the roles of different p53 oligomeric states in cancer and discuss potential research directions for overcoming aberrant p53 function associated with them. We address how misfolding and prion-like amyloid aggregation of p53 seem to play a crucial role in cancer development. The misfolded and aggregated states of mutant p53 are prospective targets for the development of novel therapeutic strategies against tumoral diseases. Full article
(This article belongs to the Special Issue Recent Advances in p53)
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Review
The Impact of Mutant p53 in the Non-Coding RNA World
Biomolecules 2020, 10(3), 472; https://doi.org/10.3390/biom10030472 - 19 Mar 2020
Cited by 6 | Viewed by 1275
Abstract
Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), micro RNAs (miRNAs), and extracellular RNAs (exRNAs) are new groups of RNAs with regulation activities that have low or no protein-coding ability. Emerging evidence suggests that deregulated expression of these non-coding RNAs is associated with the [...] Read more.
Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), micro RNAs (miRNAs), and extracellular RNAs (exRNAs) are new groups of RNAs with regulation activities that have low or no protein-coding ability. Emerging evidence suggests that deregulated expression of these non-coding RNAs is associated with the induction and progression of diverse tumors throughout epigenetic, transcriptional, and post-transcriptional modifications. A consistent number of non-coding RNAs (ncRNAs) has been shown to be regulated by p53, the most important tumor suppressor of the cells frequently mutated in human cancer. It has been shown that some mutant p53 proteins are associated with the loss of tumor suppressor activity and the acquisition of new oncogenic functions named gain-of-function activities. In this review, we highlight recent lines of evidence suggesting that mutant p53 is involved in the expression of specific ncRNAs to gain oncogenic functions through the creation of a complex network of pathways that influence each other. Full article
(This article belongs to the Special Issue Recent Advances in p53)
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Review
Role of p53 in the Regulation of Cellular Senescence
Biomolecules 2020, 10(3), 420; https://doi.org/10.3390/biom10030420 - 08 Mar 2020
Cited by 48 | Viewed by 2677
Abstract
The p53 transcription factor plays a critical role in cellular responses to stress. Its activation in response to DNA damage leads to cell growth arrest, allowing for DNA repair, or directs cellular senescence or apoptosis, thereby maintaining genome integrity. Senescence is a permanent [...] Read more.
The p53 transcription factor plays a critical role in cellular responses to stress. Its activation in response to DNA damage leads to cell growth arrest, allowing for DNA repair, or directs cellular senescence or apoptosis, thereby maintaining genome integrity. Senescence is a permanent cell-cycle arrest that has a crucial role in aging, and it also represents a robust physiological antitumor response, which counteracts oncogenic insults. In addition, senescent cells can also negatively impact the surrounding tissue microenvironment and the neighboring cells by secreting pro-inflammatory cytokines, ultimately triggering tissue dysfunction and/or unfavorable outcomes. This review focuses on the characteristics of senescence and on the recent advances in the contribution of p53 to cellular senescence. Moreover, we also discuss the p53-mediated regulation of several pathophysiological microenvironments that could be associated with senescence and its development. Full article
(This article belongs to the Special Issue Recent Advances in p53)
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Review
Mutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells
Biomolecules 2020, 10(3), 361; https://doi.org/10.3390/biom10030361 - 26 Feb 2020
Cited by 26 | Viewed by 1743
Abstract
The TP53 tumor suppressor gene is the most frequently altered gene in tumors and an increasing number of studies highlight that mutant p53 proteins can acquire oncogenic properties, referred to as gain-of-function (GOF). Reactive oxygen species (ROS) play critical roles as intracellular messengers, [...] Read more.
The TP53 tumor suppressor gene is the most frequently altered gene in tumors and an increasing number of studies highlight that mutant p53 proteins can acquire oncogenic properties, referred to as gain-of-function (GOF). Reactive oxygen species (ROS) play critical roles as intracellular messengers, regulating numerous signaling pathways linked to metabolism and cell growth. Tumor cells frequently display higher ROS levels compared to healthy cells as a result of their increased metabolism as well as serving as an oncogenic agent because of its damaging and mutational properties. Several studies reported that in contrast with the wild type protein, mutant p53 isoforms fail to exert antioxidant activities and rather increase intracellular ROS, driving a pro-tumorigenic survival. These pro-oxidant oncogenic abilities of GOF mutant p53 include signaling and metabolic rewiring, as well as the modulation of critical ROS-related transcription factors and antioxidant systems, which lead ROS unbalance linked to tumor progression. The studies summarized here highlight that GOF mutant p53 isoforms might constitute major targets for selective therapeutic intervention against several types of tumors and that ROS enhancement driven by mutant p53 might represent an “Achilles heel” of cancer cells, suggesting pro-oxidant drugs as a therapeutic approach for cancer patients bearing the mutant TP53 gene. Full article
(This article belongs to the Special Issue Recent Advances in p53)
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Review
p53’s Extended Reach: The Mutant p53 Secretome
Biomolecules 2020, 10(2), 307; https://doi.org/10.3390/biom10020307 - 15 Feb 2020
Cited by 17 | Viewed by 1703
Abstract
p53 suppresses tumorigenesis by activating a plethora of effector pathways. While most of these operate primarily inside of cells to limit proliferation and survival of incipient cancer cells, many extend to the extracellular space. In particular, p53 controls expression and secretion of numerous [...] Read more.
p53 suppresses tumorigenesis by activating a plethora of effector pathways. While most of these operate primarily inside of cells to limit proliferation and survival of incipient cancer cells, many extend to the extracellular space. In particular, p53 controls expression and secretion of numerous extracellular factors that are either soluble or contained within extracellular vesicles such as exosomes. As part of the cellular secretome, they execute key roles in cell-cell communication and extracellular matrix remodeling. Mutations in the p53-encoding TP53 gene are the most frequent genetic alterations in cancer cells, and therefore, have profound impact on the composition of the tumor cell secretome. In this review, we discuss how the loss or dominant-negative inhibition of wild-type p53 in concert with a gain of neomorphic properties observed for many mutant p53 proteins, shapes a tumor cell secretome that creates a supportive microenvironment at the primary tumor site and primes niches in distant organs for future metastatic colonization. Full article
(This article belongs to the Special Issue Recent Advances in p53)
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Review
Follow the Mutations: Toward Class-Specific, Small-Molecule Reactivation of p53
Biomolecules 2020, 10(2), 303; https://doi.org/10.3390/biom10020303 - 14 Feb 2020
Cited by 9 | Viewed by 1187
Abstract
The mutational landscape of p53 in cancer is unusual among tumor suppressors because most of the alterations are of the missense type and localize to a single domain: the ~220 amino acid DNA-binding domain. Nearly all of these mutations produce the common effect [...] Read more.
The mutational landscape of p53 in cancer is unusual among tumor suppressors because most of the alterations are of the missense type and localize to a single domain: the ~220 amino acid DNA-binding domain. Nearly all of these mutations produce the common effect of reducing p53’s ability to interact with DNA and activate transcription. Despite this seemingly simple phenotype, no mutant p53-targeted drugs are available to treat cancer patients. One of the main reasons for this is that the mutations exert their effects via multiple mechanisms—loss of DNA contacts, reduction in zinc-binding affinity, and lowering of thermodynamic stability—each of which involves a distinct type of physical impairment. This review discusses how this knowledge is informing current efforts to develop small molecules that repair these defects and restore function to mutant p53. Categorizing the spectrum of p53 mutations into discrete classes based on their inactivation mechanisms is the initial step toward personalized cancer therapy based on p53 allele status. Full article
(This article belongs to the Special Issue Recent Advances in p53)
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