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Special Issue "Emerging Non-Canonical Functions and Regulation 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 "Biochemistry, Molecular Biology and Biophysics".

Deadline for manuscript submissions: closed (30 September 2016)

Special Issue Editor

Guest Editor
Assoc. Prof. Dr. Tomoo Iwakuma

Department of Cancer Biology, University of Kansas Cancer Center, Kansas City, KS, USA
Website | E-Mail
Interests: tumor suppresssor; p53; MDM2; mutant p53; metastasis; stemness; mouse models; osteosarcoma; heat shock protein; misfolded protein

Special Issue Information

Dear Colleagues,

The tumor suppressor p53 gene is the most frequently mutated in human cancers, the majority of which are missense mutations. Mutant p53 is commonly stabilized in human cancers, causing unexpected oncogenic gain-of-function (GOF) phenotypes. The mechanisms underlying mutant p53 GOF and its stabilization have begun to emerge for the past several years. Accumulating evidence indicates that p53 is also involved in the regulation of various cellular activities, in addition to its well-known function as a regulator of cell cycle progression and Bcl-2 family protein-associated apoptosis. These include non-canonical mechanisms of cell death (calcium induced apoptosis, ferroptosis, necroptosis, autophagy, mitophagy), cell metabolism (glucose, lipid, nucleotide), immune regulation, chromosome integrity, and more. Learning these emerging functions of wild-type and mutant p53, as well as regulation of their stabilities or activities, would be crucial for deeper and more precise understanding of their roles in cell homeostasis and tumor development.

This Special Issue of the International Journal of Molecular Sciences, “Emerging Non-Canonical Functions and Regulation of p53”, will encompass a broad range of studies pertaining to recent findings in the p53 field.

Assoc. Prof. Dr. Tomoo Iwakuma
Guest Editors

Submission

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. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a 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 monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs).

Keywords

  • p53
  • mutant p53
  • non-canonical function
  • regulation
  • metabolism
  • apoptosis
  • autophagy
  • chromosome instability
  • immune regulation
  • metastasis

Published Papers (13 papers)

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Research

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Open AccessCommunication Mechanisms of p53 Functional De-Regulation: Role of the IκB-α/p53 Complex
Int. J. Mol. Sci. 2016, 17(12), 1997; doi:10.3390/ijms17121997
Received: 8 September 2016 / Revised: 23 November 2016 / Accepted: 24 November 2016 / Published: 29 November 2016
Cited by 1 | PDF Full-text (801 KB) | HTML Full-text | XML Full-text
Abstract
TP53 is one of the most frequently-mutated and deleted tumor suppressors in cancer, with a dramatic correlation with dismal prognoses. In addition to genetic inactivation, the p53 protein can be functionally inactivated in cancer, through post-transductional modifications, changes in cellular compartmentalization, and interactions
[...] Read more.
TP53 is one of the most frequently-mutated and deleted tumor suppressors in cancer, with a dramatic correlation with dismal prognoses. In addition to genetic inactivation, the p53 protein can be functionally inactivated in cancer, through post-transductional modifications, changes in cellular compartmentalization, and interactions with other proteins. Here, we review the mechanisms of p53 functional inactivation, with a particular emphasis on the interaction between p53 and IκB-α, the NFKBIA gene product. Full article
(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)
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Review

Jump to: Research

Open AccessReview Essential Roles of E3 Ubiquitin Ligases in p53 Regulation
Int. J. Mol. Sci. 2017, 18(2), 442; doi:10.3390/ijms18020442
Received: 19 November 2016 / Revised: 10 February 2017 / Accepted: 11 February 2017 / Published: 17 February 2017
PDF Full-text (928 KB) | HTML Full-text | XML Full-text
Abstract
The ubiquitination pathway and proteasomal degradation machinery dominantly regulate p53 tumor suppressor protein stability, localization, and functions in both normal and cancerous cells. Selective E3 ubiquitin ligases dominantly regulate protein levels and activities of p53 in a large range of physiological conditions and
[...] Read more.
The ubiquitination pathway and proteasomal degradation machinery dominantly regulate p53 tumor suppressor protein stability, localization, and functions in both normal and cancerous cells. Selective E3 ubiquitin ligases dominantly regulate protein levels and activities of p53 in a large range of physiological conditions and in response to cellular changes induced by exogenous and endogenous stresses. The regulation of p53’s functions by E3 ubiquitin ligases is a complex process that can lead to positive or negative regulation of p53 protein in a context- and cell type-dependent manner. Accessory proteins bind and modulate E3 ubiquitin ligases, adding yet another layer of regulatory control for p53 and its downstream functions. This review provides a comprehensive understanding of p53 regulation by selective E3 ubiquitin ligases and their potential to be considered as a new class of biomarkers and therapeutic targets in diverse types of cancers. Full article
(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)
Figures

Open AccessReview Recognition of Local DNA Structures by p53 Protein
Int. J. Mol. Sci. 2017, 18(2), 375; doi:10.3390/ijms18020375
Received: 24 November 2016 / Revised: 30 January 2017 / Accepted: 3 February 2017 / Published: 10 February 2017
PDF Full-text (1806 KB) | HTML Full-text | XML Full-text
Abstract
p53 plays critical roles in regulating cell cycle, apoptosis, senescence and metabolism and is commonly mutated in human cancer. These roles are achieved by interaction with other proteins, but particularly by interaction with DNA. As a transcription factor, p53 is well known to
[...] Read more.
p53 plays critical roles in regulating cell cycle, apoptosis, senescence and metabolism and is commonly mutated in human cancer. These roles are achieved by interaction with other proteins, but particularly by interaction with DNA. As a transcription factor, p53 is well known to bind consensus target sequences in linear B-DNA. Recent findings indicate that p53 binds with higher affinity to target sequences that form cruciform DNA structure. Moreover, p53 binds very tightly to non-B DNA structures and local DNA structures are increasingly recognized to influence the activity of wild-type and mutant p53. Apart from cruciform structures, p53 binds to quadruplex DNA, triplex DNA, DNA loops, bulged DNA and hemicatenane DNA. In this review, we describe local DNA structures and summarize information about interactions of p53 with these structural DNA motifs. These recent data provide important insights into the complexity of the p53 pathway and the functional consequences of wild-type and mutant p53 activation in normal and tumor cells. Full article
(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)
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Figure 1

Open AccessReview Targeting IRES-Mediated p53 Synthesis for Cancer Diagnosis and Therapeutics
Int. J. Mol. Sci. 2017, 18(1), 93; doi:10.3390/ijms18010093
Received: 4 October 2016 / Revised: 21 December 2016 / Accepted: 21 December 2016 / Published: 4 January 2017
PDF Full-text (407 KB) | HTML Full-text | XML Full-text
Abstract
While translational regulation of p53 by the internal ribosome entry site (IRES) at its 5′-untranslated region following DNA damage has been widely accepted, the detailed mechanism underlying the translational control of p53 by its IRES sequence is still poorly understood. In this review,
[...] Read more.
While translational regulation of p53 by the internal ribosome entry site (IRES) at its 5′-untranslated region following DNA damage has been widely accepted, the detailed mechanism underlying the translational control of p53 by its IRES sequence is still poorly understood. In this review, we will focus on the latest progress in identifying novel regulatory proteins of the p53 IRES and in uncovering the functional connection between defective IRES-mediated p53 translation and tumorigenesis. We will also discuss how these findings may lead to a better understanding of the process of oncogenesis and open up new avenues for cancer diagnosis and therapeutics. Full article
(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)
Figures

Open AccessReview p53 as a Regulator of Lipid Metabolism in Cancer
Int. J. Mol. Sci. 2016, 17(12), 2074; doi:10.3390/ijms17122074
Received: 8 October 2016 / Revised: 1 December 2016 / Accepted: 6 December 2016 / Published: 10 December 2016
PDF Full-text (937 KB) | HTML Full-text | XML Full-text
Abstract
Enhanced proliferation and survival are common features of cancer cells. Cancer cells are metabolically reprogrammed which aids in their survival in nutrient-poor environments. Indeed, changes in metabolism of glucose and glutamine are essential for tumor progression. Thus, metabolic reprogramming is now well accepted
[...] Read more.
Enhanced proliferation and survival are common features of cancer cells. Cancer cells are metabolically reprogrammed which aids in their survival in nutrient-poor environments. Indeed, changes in metabolism of glucose and glutamine are essential for tumor progression. Thus, metabolic reprogramming is now well accepted as a hallmark of cancer. Recent findings suggest that reprogramming of lipid metabolism also occurs in cancer cells, since lipids are used for biosynthesis of membranes, post-translational modifications, second messengers for signal transduction, and as a source of energy during nutrient deprivation. The tumor suppressor p53 is a transcription factor that controls the expression of proteins involved in cell cycle arrest, DNA repair, apoptosis, and senescence. p53 also regulates cellular metabolism, which appears to play a key role in its tumor suppressive activities. In this review article, we summarize non-canonical functions of wild-type and mutant p53 on lipid metabolism and discuss their association with cancer progression. Full article
(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)
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Figure 1

Open AccessReview Non-Canonical Cell Death Induced by p53
Int. J. Mol. Sci. 2016, 17(12), 2068; doi:10.3390/ijms17122068
Received: 6 October 2016 / Revised: 30 November 2016 / Accepted: 6 December 2016 / Published: 9 December 2016
PDF Full-text (3201 KB) | HTML Full-text | XML Full-text
Abstract
Programmed cell death is a vital biological process for multicellular organisms to maintain cellular homeostasis, which is regulated in a complex manner. Over the past several years, apart from apoptosis, which is the principal mechanism of caspase-dependent cell death, research on non-apoptotic forms
[...] Read more.
Programmed cell death is a vital biological process for multicellular organisms to maintain cellular homeostasis, which is regulated in a complex manner. Over the past several years, apart from apoptosis, which is the principal mechanism of caspase-dependent cell death, research on non-apoptotic forms of programmed cell death has gained momentum. p53 is a well characterized tumor suppressor that controls cell proliferation and apoptosis and has also been linked to non-apoptotic, non-canonical cell death mechanisms. p53 impacts these non-canonical forms of cell death through transcriptional regulation of its downstream targets, as well as direct interactions with key players involved in these mechanisms, in a cell type- or tissue context-dependent manner. In this review article, we summarize and discuss the involvement of p53 in several non-canonical modes of cell death, including caspase-independent apoptosis (CIA), ferroptosis, necroptosis, autophagic cell death, mitotic catastrophe, paraptosis, and pyroptosis, as well as its role in efferocytosis which is the process of clearing dead or dying cells. Full article
(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)
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Open AccessReview The Regulation of Tumor Suppressor p63 by the Ubiquitin-Proteasome System
Int. J. Mol. Sci. 2016, 17(12), 2041; doi:10.3390/ijms17122041
Received: 1 October 2016 / Revised: 23 November 2016 / Accepted: 30 November 2016 / Published: 6 December 2016
PDF Full-text (1043 KB) | HTML Full-text | XML Full-text
Abstract
The protein p63 has been identified as a homolog of the tumor suppressor protein p53 and is capable of inducing apoptosis, cell cycle arrest, or senescence. p63 has at least six isoforms, which can be divided into two major groups: the TAp63 variants
[...] Read more.
The protein p63 has been identified as a homolog of the tumor suppressor protein p53 and is capable of inducing apoptosis, cell cycle arrest, or senescence. p63 has at least six isoforms, which can be divided into two major groups: the TAp63 variants that contain the N-terminal transactivation domain and the ΔNp63 variants that lack the N-terminal transactivation domain. The TAp63 variants are generally considered to be tumor suppressors involved in activating apoptosis and suppressing metastasis. ΔNp63 variants cannot induce apoptosis but can act as dominant negative inhibitors to block the function of TAp53, TAp73, and TAp63. p63 is rarely mutated in human tumors and is predominately regulated at the post-translational level by phosphorylation and ubiquitination. This review focuses primarily on regulation of p63 by the ubiquitin E-3 ligase family of enzymes via ubiquitination and proteasome-mediated degradation, and introduces a new key regulator of the p63 protein. Full article
(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)
Figures

Open AccessReview TP53/MicroRNA Interplay in Hepatocellular Carcinoma
Int. J. Mol. Sci. 2016, 17(12), 2029; doi:10.3390/ijms17122029
Received: 13 October 2016 / Revised: 23 November 2016 / Accepted: 28 November 2016 / Published: 2 December 2016
PDF Full-text (1359 KB) | HTML Full-text | XML Full-text
Abstract
The role of microRNAs as oncogenes and tumor suppressor genes has emerged in several cancers, including hepatocellular carcinoma (HCC). The pivotal tumor suppressive role of p53-axis is indicated by the presence of inactivating mutations in TP53 gene in nearly all cancers. A close
[...] Read more.
The role of microRNAs as oncogenes and tumor suppressor genes has emerged in several cancers, including hepatocellular carcinoma (HCC). The pivotal tumor suppressive role of p53-axis is indicated by the presence of inactivating mutations in TP53 gene in nearly all cancers. A close interaction between these two players, as well as the establishment of complex p53/miRNAs loops demonstrated the strong contribution of p53-effector miRNAs in enhancing the p53-mediated tumor suppression program. On the other hand, the direct and indirect targeting of p53, as well as the regulation of its stability and activity by specific microRNAs, underlie the importance of the fine-tuning of p53 pathway, affecting the cell fate of damaged/transformed cells. The promising results of miRNAs-based therapeutic approaches in preclinical studies and their entrance in clinical trials demonstrate the feasibility of this strategy in several diseases, including cancer. Molecularly targeted drugs approved so far for HCC treatment show intrinsic or acquired resistances with disease progression in many cases, therefore the identification of effective and non-toxic agents for the treatment of HCC is actually an unmet clinical need. The knowledge of p53/miRNA inter-relations in HCC may provide useful elements for the identification of novel combined approaches in the context of the “personalized-medicine” era. Full article
(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)
Figures

Open AccessReview Molecular Mechanisms of p53 Deregulation in Cancer: An Overview in Multiple Myeloma
Int. J. Mol. Sci. 2016, 17(12), 2003; doi:10.3390/ijms17122003
Received: 29 September 2016 / Revised: 14 November 2016 / Accepted: 22 November 2016 / Published: 30 November 2016
Cited by 1 | PDF Full-text (714 KB) | HTML Full-text | XML Full-text
Abstract
The p53 pathway is inactivated in the majority of human cancers. Although this perturbation frequently occurs through the mutation or deletion of p53 itself, there are other mechanisms that can attenuate the pathway and contribute to tumorigenesis. For example, overexpression of important p53
[...] Read more.
The p53 pathway is inactivated in the majority of human cancers. Although this perturbation frequently occurs through the mutation or deletion of p53 itself, there are other mechanisms that can attenuate the pathway and contribute to tumorigenesis. For example, overexpression of important p53 negative regulators, such as murine double minute 2 (MDM2) or murine double minute 4 (MDM4), epigenetic deregulation, or even alterations in TP53 mRNA splicing. In this work, we will review the different mechanisms of p53 pathway inhibition in cancer with special focus on multiple myeloma (MM), the second most common hematological malignancy, with low incidence of p53 mutations/deletions but growing evidence of indirect p53 pathway deregulation. Translational implications for MM and cancer prognosis and treatment are also reviewed. Full article
(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)
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Open AccessReview Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemness
Int. J. Mol. Sci. 2016, 17(12), 1982; doi:10.3390/ijms17121982
Received: 29 September 2016 / Revised: 10 November 2016 / Accepted: 15 November 2016 / Published: 26 November 2016
PDF Full-text (3822 KB) | HTML Full-text | XML Full-text
Abstract
Since its discovery nearly 40 years ago, p53 has ascended to the forefront of investigated genes and proteins across diverse research disciplines and is recognized most exclusively for its role in cancer as a tumor suppressor. Levine and Oren (2009) reviewed the evolution
[...] Read more.
Since its discovery nearly 40 years ago, p53 has ascended to the forefront of investigated genes and proteins across diverse research disciplines and is recognized most exclusively for its role in cancer as a tumor suppressor. Levine and Oren (2009) reviewed the evolution of p53 detailing the significant discoveries of each decade since its first report in 1979. In this review, we will highlight the emerging non-canonical functions and regulation of p53 in stem cells. We will focus on general themes shared among p53’s functions in non-malignant stem cells and cancer stem-like cells (CSCs) and the influence of p53 on the microenvironment and CSC niche. We will also examine p53 gain of function (GOF) roles in stemness. Mutant p53 (mutp53) GOFs that lead to survival, drug resistance and colonization are reviewed in the context of the acquisition of advantageous transformation processes, such as differentiation and dedifferentiation, epithelial-to-mesenchymal transition (EMT) and stem cell senescence and quiescence. Finally, we will conclude with therapeutic strategies that restore wild-type p53 (wtp53) function in cancer and CSCs, including RING finger E3 ligases and CSC maintenance. The mechanisms by which wtp53 and mutp53 influence stemness in non-malignant stem cells and CSCs or tumor-initiating cells (TICs) are poorly understood thus far. Further elucidation of p53’s effects on stemness could lead to novel therapeutic strategies in cancer research. Full article
(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)
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Open AccessReview The Double Role of p53 in Cancer and Autoimmunity and Its Potential as Therapeutic Target
Int. J. Mol. Sci. 2016, 17(12), 1975; doi:10.3390/ijms17121975
Received: 13 September 2016 / Revised: 7 November 2016 / Accepted: 17 November 2016 / Published: 25 November 2016
PDF Full-text (1010 KB) | HTML Full-text | XML Full-text
Abstract
p53 is a sequence-specific short-lived transcription factor expressed at low concentrations in various tissues while it is upregulated in damaged, tumoral or inflamed tissue. In normally proliferating cells, p53 protein levels and function are tightly controlled by main regulators, i.e., MDM2 (mouse double
[...] Read more.
p53 is a sequence-specific short-lived transcription factor expressed at low concentrations in various tissues while it is upregulated in damaged, tumoral or inflamed tissue. In normally proliferating cells, p53 protein levels and function are tightly controlled by main regulators, i.e., MDM2 (mouse double minute 2) and MDM4 proteins. p53 plays an important role due to its ability to mediate tumor suppression. In addition to its importance as a tumor suppressor, p53 coordinates diverse cellular responses to stress and damage and plays an emerging role in various physiological processes, including fertility, cell metabolism, mitochondrial respiration, autophagy, cell adhesion, stem cell maintenance and development. Interestingly, it has been recently implicated in the suppression of autoimmune and inflammatory diseases in both mice and humans. In this review based on current knowledge on the functional properties of p53 and its regulatory pathways, we discuss the potential utility of p53 reactivation from a therapeutic perspective in oncology and chronic inflammatory disorders leading to autoimmunity. Full article
(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)
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Open AccessReview Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment
Int. J. Mol. Sci. 2016, 17(11), 1942; doi:10.3390/ijms17111942
Received: 3 October 2016 / Revised: 7 November 2016 / Accepted: 10 November 2016 / Published: 19 November 2016
PDF Full-text (1115 KB) | HTML Full-text | XML Full-text
Abstract
The tumor suppressor p53 is the most frequently mutated gene in human cancers. Most of the mutations are missense leading to loss of p53 function in inducing apoptosis and senescence. In addition to these autonomous effects of p53 inactivation/dysfunction on tumorigenesis, compelling evidence
[...] Read more.
The tumor suppressor p53 is the most frequently mutated gene in human cancers. Most of the mutations are missense leading to loss of p53 function in inducing apoptosis and senescence. In addition to these autonomous effects of p53 inactivation/dysfunction on tumorigenesis, compelling evidence suggests that p53 mutation/inactivation also leads to gain-of-function or activation of non-autonomous pathways, which either directly or indirectly promote tumorigenesis. Experimental and clinical results suggest that p53 dysfunction fuels pro-tumor inflammation and serves as an immunological gain-of-function driver of tumorigenesis via skewing immune landscape of the tumor microenvironment (TME). It is now increasingly appreciated that p53 dysfunction in various cellular compartments of the TME leads to immunosuppression and immune evasion. Although our understanding of the cellular and molecular processes that link p53 activity to host immune regulation is still incomplete, it is clear that activating/reactivating the p53 pathway in the TME also represents a compelling immunological strategy to reverse immunosuppression and enhance antitumor immunity. Here, we review our current understanding of the potential cellular and molecular mechanisms by which p53 participates in immune regulation and discuss how targeting the p53 pathway can be exploited to alter the immunological landscape of tumors for maximizing therapeutic outcome. Full article
(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)
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Figure 1

Open AccessReview p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure–Function Continuum Concept
Int. J. Mol. Sci. 2016, 17(11), 1874; doi:10.3390/ijms17111874
Received: 19 September 2016 / Revised: 27 October 2016 / Accepted: 3 November 2016 / Published: 10 November 2016
PDF Full-text (8023 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Although it is one of the most studied proteins, p53 continues to be an enigma. This protein has numerous biological functions, possesses intrinsically disordered regions crucial for its functionality, can form both homo-tetramers and isoform-based hetero-tetramers, and is able to interact with many
[...] Read more.
Although it is one of the most studied proteins, p53 continues to be an enigma. This protein has numerous biological functions, possesses intrinsically disordered regions crucial for its functionality, can form both homo-tetramers and isoform-based hetero-tetramers, and is able to interact with many binding partners. It contains numerous posttranslational modifications, has several isoforms generated by alternative splicing, alternative promoter usage or alternative initiation of translation, and is commonly mutated in different cancers. Therefore, p53 serves as an important illustration of the protein structure–function continuum concept, where the generation of multiple proteoforms by various mechanisms defines the ability of this protein to have a multitude of structurally and functionally different states. Considering p53 in the light of a proteoform-based structure–function continuum represents a non-canonical and conceptually new contemplation of structure, regulation, and functionality of this important protein. Full article
(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)
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