International Journal of Molecular Sciences

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Open AccessEditorial

Emerging Non-Canonical Functions and Regulation of p53

by Atul Ranjan and Tomoo Iwakuma

Int. J. Mol. Sci. 2018, 19(4), 1015; https://doi.org/10.3390/ijms19041015 - 28 Mar 2018

Cited by 7 | Viewed by 3396

Abstract

The tumor suppressor p53 induces cell cycle arrest and/or apoptosis by transactivating numerous downstream target genes and also translocating to the mitochondrial outer membrane. Full article

(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)

Research

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Mechanisms of p53 Functional De-Regulation: Role of the IκB-α/p53 Complex

by Giovanna Carrà, Sabrina Crivellaro, Riccardo Taulli, Angelo Guerrasio, Giuseppe Saglio and Alessandro Morotti

Int. J. Mol. Sci. 2016, 17(12), 1997; https://doi.org/10.3390/ijms17121997 - 29 Nov 2016

Cited by 14 | Viewed by 5024

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

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22 pages, 4510 KiB

Open AccessReview

Emerging Roles of p53 Family Members in Glucose Metabolism

by Yoko Itahana and Koji Itahana

Int. J. Mol. Sci. 2018, 19(3), 776; https://doi.org/10.3390/ijms19030776 - 8 Mar 2018

Cited by 96 | Viewed by 8859

Abstract

Glucose is the key source for most organisms to provide energy, as well as the key source for metabolites to generate building blocks in cells. The deregulation of glucose homeostasis occurs in various diseases, including the enhanced aerobic glycolysis that is observed in [...] Read more.

Glucose is the key source for most organisms to provide energy, as well as the key source for metabolites to generate building blocks in cells. The deregulation of glucose homeostasis occurs in various diseases, including the enhanced aerobic glycolysis that is observed in cancers, and insulin resistance in diabetes. Although p53 is thought to suppress tumorigenesis primarily by inducing cell cycle arrest, apoptosis, and senescence in response to stress, the non-canonical functions of p53 in cellular energy homeostasis and metabolism are also emerging as critical factors for tumor suppression. Increasing evidence suggests that p53 plays a significant role in regulating glucose homeostasis. Furthermore, the p53 family members p63 and p73, as well as gain-of-function p53 mutants, are also involved in glucose metabolism. Indeed, how this protein family regulates cellular energy levels is complicated and difficult to disentangle. This review discusses the roles of the p53 family in multiple metabolic processes, such as glycolysis, gluconeogenesis, aerobic respiration, and autophagy. We also discuss how the dysregulation of the p53 family in these processes leads to diseases such as cancer and diabetes. Elucidating the complexities of the p53 family members in glucose homeostasis will improve our understanding of these diseases. Full article

(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)

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Control of Nucleotide Metabolism Enables Mutant p53’s Oncogenic Gain-of-Function Activity

by Valentina Schmidt, Rachana Nagar and Luis A. Martinez

Int. J. Mol. Sci. 2017, 18(12), 2759; https://doi.org/10.3390/ijms18122759 - 19 Dec 2017

Cited by 14 | Viewed by 7066

Abstract

Since its discovery as an oncoprotein in 1979, investigation into p53’s many identities has completed a full circle and today it is inarguably the most extensively studied tumor suppressor (wild-type p53 form or WTp53) and oncogene (mutant p53 form or mtp53) in cancer [...] Read more.

Since its discovery as an oncoprotein in 1979, investigation into p53’s many identities has completed a full circle and today it is inarguably the most extensively studied tumor suppressor (wild-type p53 form or WTp53) and oncogene (mutant p53 form or mtp53) in cancer research. After the p53 protein was declared “Molecule of the Year” by Science in 1993, the p53 field exploded and a plethora of excellent reviews is now available on every aspect of p53 genetics and functional repertoire in a cell. Nevertheless, new functions of p53 continue to emerge. Here, we discuss a novel mechanism that contributes to mtp53’s Gain of Functions GOF (gain-of-function) activities and involves the upregulation of both nucleotide de novo synthesis and nucleoside salvage pathways. Full article

(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)

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Mutant p53 Protein and the Hippo Transducers YAP and TAZ: A Critical Oncogenic Node in Human Cancers

by Maria Ferraiuolo, Lorena Verduci, Giovanni Blandino and Sabrina Strano

Int. J. Mol. Sci. 2017, 18(5), 961; https://doi.org/10.3390/ijms18050961 - 3 May 2017

Cited by 42 | Viewed by 10425

Abstract

p53 protein is a well-known tumor suppressor factor that regulates cellular homeostasis. As it has several and key functions exerted, p53 is known as “the guardian of the genome” and either loss of function or gain of function mutations in the TP53 coding [...] Read more.

p53 protein is a well-known tumor suppressor factor that regulates cellular homeostasis. As it has several and key functions exerted, p53 is known as “the guardian of the genome” and either loss of function or gain of function mutations in the TP53 coding protein sequence are involved in cancer onset and progression. The Hippo pathway is a key regulator of developmental and regenerative physiological processes but if deregulated can induce cell transformation and cancer progression. The p53 and Hippo pathways exert a plethora of fine-tuned functions that can apparently be in contrast with each other. In this review, we propose that the p53 status can affect the Hippo pathway function by switching its outputs from tumor suppressor to oncogenic activities. In detail, we discuss: (a) the oncogenic role of the protein complex mutant p53/YAP; (b) TAZ oncogenic activation mediated by mutant p53; (c) the therapeutic potential of targeting mutant p53 to impair YAP and TAZ oncogenic functions in human cancers. Full article

(This article belongs to the Special Issue Emerging Non-Canonical Functions and Regulation of p53)

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Essential Roles of E3 Ubiquitin Ligases in p53 Regulation

by Sanam Sane and Khosrow Rezvani

Int. J. Mol. Sci. 2017, 18(2), 442; https://doi.org/10.3390/ijms18020442 - 17 Feb 2017

Cited by 59 | Viewed by 9050

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)

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Recognition of Local DNA Structures by p53 Protein

by Václav Brázda and Jan Coufal

Int. J. Mol. Sci. 2017, 18(2), 375; https://doi.org/10.3390/ijms18020375 - 10 Feb 2017

Cited by 32 | Viewed by 8740 | Correction

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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Open AccessReview

Targeting IRES-Mediated p53 Synthesis for Cancer Diagnosis and Therapeutics

by Bai Ji, Benjamin R. E. Harris, Yahui Liu, Yibin Deng, Sergio A. Gradilone, Margot P. Cleary, Jianhua Liu and Da-Qing Yang

Int. J. Mol. Sci. 2017, 18(1), 93; https://doi.org/10.3390/ijms18010093 - 4 Jan 2017

Cited by 20 | Viewed by 7064

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)

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p53 as a Regulator of Lipid Metabolism in Cancer

by Alejandro Parrales and Tomoo Iwakuma

Int. J. Mol. Sci. 2016, 17(12), 2074; https://doi.org/10.3390/ijms17122074 - 10 Dec 2016

Cited by 75 | Viewed by 10668

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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Non-Canonical Cell Death Induced by p53

by Atul Ranjan and Tomoo Iwakuma

Int. J. Mol. Sci. 2016, 17(12), 2068; https://doi.org/10.3390/ijms17122068 - 9 Dec 2016

Cited by 107 | Viewed by 16606

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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The Regulation of Tumor Suppressor p63 by the Ubiquitin-Proteasome System

by Stephen R. Armstrong, Hong Wu, Benfan Wang, Yasser Abuetabh, Consolato Sergi and Roger P. Leng

Int. J. Mol. Sci. 2016, 17(12), 2041; https://doi.org/10.3390/ijms17122041 - 6 Dec 2016

Cited by 36 | Viewed by 7417

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)

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TP53/MicroRNA Interplay in Hepatocellular Carcinoma

by Daniela Pollutri, Laura Gramantieri, Luigi Bolondi and Francesca Fornari

Int. J. Mol. Sci. 2016, 17(12), 2029; https://doi.org/10.3390/ijms17122029 - 2 Dec 2016

Cited by 28 | Viewed by 7421

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)

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Molecular Mechanisms of p53 Deregulation in Cancer: An Overview in Multiple Myeloma

by Ana B. Herrero, Elizabeta A. Rojas, Irena Misiewicz-Krzeminska, Patryk Krzeminski and Norma C. Gutiérrez

Int. J. Mol. Sci. 2016, 17(12), 2003; https://doi.org/10.3390/ijms17122003 - 30 Nov 2016

Cited by 69 | Viewed by 12578

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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Emerging Non-Canonical Functions and Regulation by p53: p53 and Stemness

by David J. Olivos and Lindsey D. Mayo

Int. J. Mol. Sci. 2016, 17(12), 1982; https://doi.org/10.3390/ijms17121982 - 26 Nov 2016

Cited by 46 | Viewed by 9347

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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The Double Role of p53 in Cancer and Autoimmunity and Its Potential as Therapeutic Target

by Alessandra Fierabracci and Marsha Pellegrino

Int. J. Mol. Sci. 2016, 17(12), 1975; https://doi.org/10.3390/ijms17121975 - 25 Nov 2016

Cited by 23 | Viewed by 7873

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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Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment

by Yan Cui and Gang Guo

Int. J. Mol. Sci. 2016, 17(11), 1942; https://doi.org/10.3390/ijms17111942 - 19 Nov 2016

Cited by 96 | Viewed by 20793

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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p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure–Function Continuum Concept

by Vladimir N. Uversky

Int. J. Mol. Sci. 2016, 17(11), 1874; https://doi.org/10.3390/ijms17111874 - 10 Nov 2016

Cited by 140 | Viewed by 12254

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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