Cancers

Research

25 pages, 6163 KiB

Open AccessArticle

Altered Expression of Shorter p53 Family Isoforms Can Impact Melanoma Aggressiveness

by Ana Tadijan, Francesca Precazzini, Nikolina Hanžić, Martina Radić, Nicolò Gavioli, Ignacija Vlašić, Petar Ozretić, Lia Pinto, Lidija Škreblin, Giulia Barban, Neda Slade and Yari Ciribilli

Cancers 2021, 13(20), 5231; https://doi.org/10.3390/cancers13205231 - 18 Oct 2021

Cited by 17 | Viewed by 4701

Abstract

Cutaneous melanoma is the most aggressive form of skin cancer. Despite the significant advances in the management of melanoma in recent decades, it still represents a challenge for clinicians. The TP53 gene, the guardian of the genome, which is altered in more than [...] Read more.

Cutaneous melanoma is the most aggressive form of skin cancer. Despite the significant advances in the management of melanoma in recent decades, it still represents a challenge for clinicians. The TP53 gene, the guardian of the genome, which is altered in more than 50% of human cancers, is rarely mutated in melanoma. More recently, researchers started to appreciate the importance of shorter p53 isoforms as potential modifiers of the p53-dependent responses. We analyzed the expression of p53 and p73 isoforms both at the RNA and protein level in a panel of melanoma-derived cell lines with different TP53 and BRAF status, in normal conditions or upon treatment with common anti-cancer DNA damaging agents or targeted therapy. Using lentiviral vectors, we also generated stable clones of H1299 p53 null cells over-expressing the less characterized isoforms Δ160p53α, Δ160p53β, and Δ160p53γ. Further, we obtained two melanoma-derived cell lines resistant to BRAF inhibitor vemurafenib. We observed that melanoma cell lines expressed a wide array of p53 and p73 isoforms, with Δ160p53α as the most variable one. We demonstrated for the first time that Δ160p53α, and to a lesser extent Δ160p53β, can be recruited on chromatin, and that Δ160p53γ can localize in perinuclear foci; moreover, all Δ160p53 isoforms can stimulate proliferation and in vitro migration. Lastly, vemurafenib-resistant melanoma cells showed an altered expression of p53 and p73 isoforms, namely an increased expression of potentially pro-oncogenic Δ40p53β and a decrease in tumor-suppressive TAp73β. We therefore propose that p53 family isoforms can play a role in melanoma cells’ aggressiveness. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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27 pages, 10078 KiB

Open AccessArticle

Deciphering the Nature of Trp73 Isoforms in Mouse Embryonic Stem Cell Models: Generation of Isoform-Specific Deficient Cell Lines Using the CRISPR/Cas9 Gene Editing System

by Lorena López-Ferreras, Nicole Martínez-García, Laura Maeso-Alonso, Marta Martín-López, Ángela Díez-Matilla, Javier Villoch-Fernandez, Hugo Alonso-Olivares, Margarita M. Marques and Maria C. Marin

Cancers 2021, 13(13), 3182; https://doi.org/10.3390/cancers13133182 - 25 Jun 2021

Cited by 6 | Viewed by 4734

Abstract

The p53 family has been widely studied for its role in various physiological and pathological processes. Imbalance of p53 family proteins may contribute to developmental abnormalities and pathologies in humans. This family exerts its functions through a profusion of isoforms that are generated [...] Read more.

The p53 family has been widely studied for its role in various physiological and pathological processes. Imbalance of p53 family proteins may contribute to developmental abnormalities and pathologies in humans. This family exerts its functions through a profusion of isoforms that are generated by different promoter usage and alternative splicing in a cell type dependent manner. In particular, the Trp73 gene gives rise to TA and DN-p73 isoforms that confer p73 a dual nature. The biological relevance of p73 does not only rely on its tumor suppression effects, but on its pivotal role in several developmental processes. Therefore, the generation of cellular models that allow the study of the individual isoforms in a physiological context is of great biomedical relevance. We generated specific TA and DN-p73-deficient mouse embryonic stem cell lines using the CRISPR/Cas9 gene editing system and validated them as physiological bona fide p73-isoform knockout models. Global gene expression analysis revealed isoform-specific alterations of distinctive transcriptional networks. Elimination of TA or DN-p73 is compatible with pluripotency but prompts naïve pluripotent stem cell transition into the primed state, compromising adequate lineage differentiation, thus suggesting that differential expression of p73 isoforms acts as a rheostat during early cell fate determination. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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14 pages, 1986 KiB

Open AccessArticle

Small Proline-Rich Protein 2A and 2D Are Regulated by the RBM38-p73 Axis and Associated with p73-Dependent Suppression of Chronic Inflammation

by Xiangmudong Kong, Dan Wang, Wenqiang Sun, Mingyi Chen, Jinhui Chen, Jisen Shi, Jin Zhang and Xinbin Chen

Cancers 2021, 13(11), 2829; https://doi.org/10.3390/cancers13112829 - 6 Jun 2021

Cited by 2 | Viewed by 3189

Abstract

Small proline-rich protein 2A and 2D (SPRR2A and SPRR2D) provide barrier function in terminally differentiated stratified squamous epithelia through the epidermal differentiation complex. However, little is known how SPRR2A/2D expression is controlled and their role in chronic inflammation. Here, we showed that that [...] Read more.

Small proline-rich protein 2A and 2D (SPRR2A and SPRR2D) provide barrier function in terminally differentiated stratified squamous epithelia through the epidermal differentiation complex. However, little is known how SPRR2A/2D expression is controlled and their role in chronic inflammation. Here, we showed that that SPRR2A/2D expression is controlled by a regulatory loop formed by RNA-binding protein RBM38 and tumor suppressor p73. Specifically, we found that SPRR2A/2D expression was induced by ectopic expression of RBM38 or p73 but suppressed by knockout of Rbm38 or p73. We also found that RBM38-mediated expression of SPRR2A/2D was p73-dependent and that induction of SPRR2A/2D during keratinocyte differentiation was dependent on both p73 and Rbm38. Additionally, we found that SPRR2A/2D expression was closely associated with p73 expression in normal and cancerous tissues. To determine the biological function of the RBM38-p73 loop potentially via SPRR2A/2D, we generated a cohort of wild-type, Rbm38^−/−, Trp73^+/−, and Rbm38^−/−;Trp73^+/− mice. We found that Rbm38^−/−;Trp73^+/− mice had a much shorter lifespan than that for Rbm38^−/−—and to a lesser extent for Trp73^+/− mice—but were less prone to spontaneous tumors than Trp73^+/− or Rbm38^−/− mice. We also found that Rbm38^−/−;Trp73^+/− mice exhibited weak expression of SPRR2A/2D in multiple tissues and were susceptible to systemic chronic inflammation, suggesting that decreased SPRR2A/2D expression is likely responsible for chronic inflammation in Rbm38^−/−;Trp73^+/− mice, leading to a shortened lifespan. Together, our data reveal that SPRR2A/2D are novel targets of the RBM38-p73 loop and contribute to p73-dependent suppression of chronic inflammation. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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14 pages, 1773 KiB

Open AccessArticle

ΔNp73, TAp73 and Δ133p53 Extracellular Vesicle Cargo as Early Diagnosis Markers in Colorectal Cancer

by Javier Rodríguez-Cobos, David Viñal, Carmen Poves, María J. Fernández-Aceñero, Héctor Peinado, Daniel Pastor-Morate, Mª Isabel Prieto, Rodrigo Barderas, Nuria Rodríguez-Salas and Gemma Domínguez

Cancers 2021, 13(9), 2240; https://doi.org/10.3390/cancers13092240 - 7 May 2021

Cited by 7 | Viewed by 2650

Abstract

The early diagnosis of colorectal cancer is a key factor in the overall survival of the patients. The actual screening programs include different approaches with significant limitations such as unspecificity, high invasiveness, and detection at late stages of the disease. The specific content [...] Read more.

The early diagnosis of colorectal cancer is a key factor in the overall survival of the patients. The actual screening programs include different approaches with significant limitations such as unspecificity, high invasiveness, and detection at late stages of the disease. The specific content of extracellular vesicles derived from malignant cells may represent a non-invasive technique for the early detection of colorectal cancer. Here, we studied the mRNA levels of ΔNp73, TAp73, and Δ133p53 in plasma-derived extracellular vesicles from healthy subjects (n = 29), individuals with premalignant lesions (n = 49), and colorectal cancer patients (n = 42). Extracellular vesicles’ ΔNp73 levels were already significantly high in subjects with premalignant lesions. Δ133p53 levels were statistically increased in colorectal cancer patients compared to the other two groups and were associated with patients’ survival. Remarkably, TAp73 mRNA was not detected in any of the individuals. The evaluation of ΔNp73, Δ133p53 and CEA sensitivity, specificity and AUC values supports ΔNp73 as a better early diagnosis biomarker and CEA as the best to identify advanced stages. Thus, low levels of CEA and a high content of ΔNp73 may identify in screening programs those individuals at higher risk of presenting a premalignant lesion. In addition, Δ133p53 emerges as a potential prognosis biomarker in colorectal cancer. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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18 pages, 3606 KiB

Open AccessArticle

Breast Cancer Patient Prognosis Is Determined by the Interplay between TP53 Mutation and Alternative Transcript Expression: Insights from TP53 Long Amplicon Digital PCR Assays

by Annette Lasham, Nicholas Knowlton, Sunali Y. Mehta, Antony W. Braithwaite and Cristin G. Print

Cancers 2021, 13(7), 1531; https://doi.org/10.3390/cancers13071531 - 26 Mar 2021

Cited by 8 | Viewed by 3591

Abstract

The TP53 gene locus is capable of producing multiple RNA transcripts encoding the different p53 protein isoforms. We recently described multiplex long amplicon droplet digital PCR (ddPCR) assays to quantify seven of eight TP53 reference transcripts in human tumors. Here, we describe a [...] Read more.

The TP53 gene locus is capable of producing multiple RNA transcripts encoding the different p53 protein isoforms. We recently described multiplex long amplicon droplet digital PCR (ddPCR) assays to quantify seven of eight TP53 reference transcripts in human tumors. Here, we describe a new long amplicon ddPCR assay to quantify expression of the eighth TP53 reference transcript encoding ∆40p53α. We then applied these assays, alongside DNA sequencing of the TP53 gene locus, to tumors from a cohort of New Zealand (NZ) breast cancer patients. We found a high prevalence of mutations at TP53 splice sites in the NZ breast cancer cohort. Mutations at TP53 intron 4 splice sites were associated with overexpression of ∆133TP53 transcripts. Cox proportional hazards survival analysis showed that interplay between TP53 mutation status and expression of TP53 transcript variants was significantly associated with patient outcome, over and above standard clinical and pathological information. In particular, patients with no TP53 mutation and a low ratio of TP53 transcripts t2 to t1, which derive from alternative intron 1 acceptor splice sites, had a remarkably good outcome. We suggest that this type of analysis, integrating mutation and transcript expression, provides a step-change in our understanding of TP53 in cancer. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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19 pages, 25070 KiB

Open AccessArticle

TAp73β Can Promote Hepatocellular Carcinoma Dedifferentiation

by Evin Iscan, Umut Ekin, Gokhan Yildiz, Ozden Oz, Umur Keles, Aslı Suner, Gulcin Cakan-Akdogan, Gunes Ozhan, Marta Nekulova, Borivoj Vojtesek, Hamdiye Uzuner, Gökhan Karakülah, Hani Alotaibi and Mehmet Ozturk

Cancers 2021, 13(4), 783; https://doi.org/10.3390/cancers13040783 - 13 Feb 2021

Cited by 11 | Viewed by 5308

Abstract

Hepatocyte dedifferentiation is a major source of hepatocellular carcinoma (HCC), but its mechanisms are unknown. We explored the p73 expression in HCC tumors and studied the effects of transcriptionally active p73β (TAp73β) in HCC cells. Expression profiles of p73 and patient clinical data [...] Read more.

Hepatocyte dedifferentiation is a major source of hepatocellular carcinoma (HCC), but its mechanisms are unknown. We explored the p73 expression in HCC tumors and studied the effects of transcriptionally active p73β (TAp73β) in HCC cells. Expression profiles of p73 and patient clinical data were collected from the Genomic Data Commons (GDC) data portal and the TSVdb database, respectively. Global gene expression profiles were determined by pan-genomic 54K microarrays. The Gene Set Enrichment Analysis method was used to identify TAp73β-regulated gene sets. The effects of TAp73 isoforms were analyzed in monolayer cell culture, 3D-cell culture and xenograft models in zebrafish using western blot, flow cytometry, fluorescence imaging, real-time polymerase chain reaction (RT-PCR), immunohistochemistry and morphological examination. TAp73 isoforms were significantly upregulated in HCC, and high p73 expression correlated with poor patient survival. The induced expression of TAp73β caused landscape expression changes in genes involved in growth signaling, cell cycle, stress response, immunity, metabolism and development. Hep3B cells overexpressing TAp73β had lost hepatocyte lineage biomarkers including ALB, CYP3A4, AFP, HNF4α. In contrast, TAp73β upregulated genes promoting cholangiocyte lineage such as YAP, JAG1 and ZO-1, accompanied with an increase in metastatic ability. Our findings suggest that TAp73β may promote malignant dedifferentiation of HCC cells. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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15 pages, 3431 KiB

Open AccessArticle

Single Cell Detection of the p53 Protein by Mass Cytometry

by Oda Helen Eck Fagerholt, Monica Hellesøy, Stein-Erik Gullaksen and Bjørn Tore Gjertsen

Cancers 2020, 12(12), 3699; https://doi.org/10.3390/cancers12123699 - 9 Dec 2020

Cited by 4 | Viewed by 4358

Abstract

Purpose: The p53 protein and its post-translational modifications are distinctly expressed in various normal cell types and malignant cells and are usually detected by immunohistochemistry and flow cytometry in contemporary diagnostics. Here, we describe an approach for simultaneous multiparameter detection of p53, its [...] Read more.

Purpose: The p53 protein and its post-translational modifications are distinctly expressed in various normal cell types and malignant cells and are usually detected by immunohistochemistry and flow cytometry in contemporary diagnostics. Here, we describe an approach for simultaneous multiparameter detection of p53, its post-translational modifications and p53 pathway-related signaling proteins in single cells using mass cytometry. Method: We conjugated p53-specific antibodies to metal tags for detection by mass cytometry, allowing the detection of proteins and their post-translational modifications in single cells. We provide an overview of the antibody validation process using relevant biological controls, including cell lines treated in vitro with a stimulus (irradiation) known to induce changes in the expression level of p53. Finally, we present the potential of the method through investigation of primary samples from leukemia patients with distinct TP53 mutational status. Results: The p53 protein can be detected in cell lines and in primary samples by mass cytometry. By combining antibodies for p53-related signaling proteins with a surface marker panel, we show that mass cytometry can be used to decipher the single cell p53 signaling pathway in heterogeneous patient samples. Conclusion: Single cell profiling by mass cytometry allows the investigation of the p53 functionality through examination of relevant downstream signaling proteins in normal and malignant cells. Our work illustrates a novel approach for single cell profiling of p53. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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14 pages, 2362 KiB

Open AccessArticle

A Comparison of p53 Isoform Profiles and Apoptosis Induced by Camptothecin or a Herbal Khat Extract (Catha Edulis (Vahl) Forssk. ex Endl.) in Leukemic Cell Lines: Exploring Cellular Responses in Therapy Development

by Therese Bredholt Onyango, Sigrun M. Hjelle, Ingvild Haaland, Olav K. Vintermyr, Anne Christine Johannessen and Bjørn Tore Gjertsen

Cancers 2020, 12(12), 3596; https://doi.org/10.3390/cancers12123596 - 1 Dec 2020

Cited by 2 | Viewed by 3340

Abstract

Khat (Catha edulis (Vahl) Forssk. ex Endl.) is habitually used as a natural stimulant by millions of people, but is associated with adverse effects on gastrointestinal, cardiovascular and central neural systems. At the cellular level khat toxicity involves p53 induction and [...] Read more.

Khat (Catha edulis (Vahl) Forssk. ex Endl.) is habitually used as a natural stimulant by millions of people, but is associated with adverse effects on gastrointestinal, cardiovascular and central neural systems. At the cellular level khat toxicity involves p53 induction and cell cycle arrest, decreased mitochondrial function and activation of receptor- and mitochondria-mediated cell death pathways. In this study we have examined an extract of khat for induction of p53 post-translational modifications (PTMs) and the functional role of p53 in khat-mediated cell death. Khat was shown to induce phosphorylation and acetylation of p53 in both the khat-sensitive MOLM-13 and the khat-resistant MV-4-11 cell line, but accumulation of the full-length p53 isoform was only observed in the khat sensitive cell line. Small molecule inhibitors of p38 MAP kinase sensitized MV-4-11 cells for khat-treatment without concomitant stabilization of p53. Experiments using a p53 knock-down cell line and murine p53 knock-out bone marrow cells indicated that p53 was redundant in khat-mediated cell death in vitro. We suggest that analysis of isoform patterns and p53 PTMs are useful for elucidation of biological effects of complex plant extracts, and that p53 protein analysis is particularly useful in the search for new chemical probes and experimental cancer therapeutics. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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18 pages, 2660 KiB

Open AccessFeature PaperArticle

Intronic TP53 Polymorphisms Are Associated with Increased Δ133TP53 Transcript, Immune Infiltration and Cancer Risk

by Ramona A. Eiholzer, Sunali Mehta, Marina Kazantseva, Catherine J. Drummond, Cushla McKinney, Katie Young, David Slater, Brianna C. Morten, Kelly A. Avery-Kiejda, Annette Lasham, Nicholas Fleming, Helen R. Morrin, Karen Reader, Janice A. Royds, Michael Landmann, Simone Petrich, Roger Reddel, Lily Huschtscha, Ahmad Taha, Noelyn A. Hung, Tania L. Slatter and Antony W. Braithwaite Show full author list Hide full author list

Cancers 2020, 12(9), 2472; https://doi.org/10.3390/cancers12092472 - 1 Sep 2020

Cited by 18 | Viewed by 5242

Abstract

We investigated the influence of selected TP53 SNPs in exon 4 and intron 4 on cancer risk, clinicopathological features and expression of TP53 isoforms. The intron 4 SNPs were significantly over-represented in cohorts of mixed cancers compared to three ethnically matched controls, suggesting [...] Read more.

We investigated the influence of selected TP53 SNPs in exon 4 and intron 4 on cancer risk, clinicopathological features and expression of TP53 isoforms. The intron 4 SNPs were significantly over-represented in cohorts of mixed cancers compared to three ethnically matched controls, suggesting they confer increased cancer risk. Further analysis showed that heterozygosity at rs1042522(GC) and either of the two intronic SNPs rs9895829(TC) and rs2909430(AG) confer a 2.34–5.35-fold greater risk of developing cancer. These SNP combinations were found to be associated with shorter patient survival for glioblastoma and prostate cancer. Additionally, these SNPs were associated with tumor-promoting inflammation as evidenced by high levels of infiltrating immune cells and expression of the Δ133TP53 and TP53β transcripts. We propose that these SNP combinations allow increased expression of the Δ133p53 isoforms to promote the recruitment of immune cells that create an immunosuppressive environment leading to cancer progression. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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18 pages, 3883 KiB

Open AccessArticle

Accessing a New Dimension in TP53 Biology: Multiplex Long Amplicon Digital PCR to Specifically Detect and Quantitate Individual TP53 Transcripts

by Annette Lasham, Peter Tsai, Sandra J. Fitzgerald, Sunali Y. Mehta, Nicholas S. Knowlton, Antony W. Braithwaite and Cristin G. Print

Cancers 2020, 12(3), 769; https://doi.org/10.3390/cancers12030769 - 24 Mar 2020

Cited by 11 | Viewed by 5318

Abstract

TP53, the most commonly-mutated gene in cancer, undergoes complex alternative splicing. Different TP53 transcripts play different biological roles, both in normal function and in the progression of diseases such as cancer. The study of TP53’s alternative RNA splice forms and their use [...] Read more.

TP53, the most commonly-mutated gene in cancer, undergoes complex alternative splicing. Different TP53 transcripts play different biological roles, both in normal function and in the progression of diseases such as cancer. The study of TP53’s alternative RNA splice forms and their use as clinical biomarkers has been hampered by limited specificity and quantitative accuracy of current methods. TP53 RNA splice variants differ at both 5’ and 3’ ends, but because they have a common central region of 618 bp, the individual TP53 transcripts are impossible to specifically detect and precisely quantitate using standard PCR-based methods or short-read RNA sequencing. Therefore, we devised multiplex probe-based long amplicon droplet digital PCR (ddPCR) assays, which for the first time allow precise end-to-end quantitation of the seven major TP53 transcripts, with amplicons ranging from 0.85 to 1.85 kb. Multiple modifications to standard ddPCR assay procedures were required to enable specific co-amplification of these long transcripts and to overcome issues with secondary structure. Using these assays, we show that several TP53 transcripts are co-expressed in breast cancers, and illustrate the potential for this method to identify novel TP53 transcripts in tumour cells. This capability will facilitate a new level of biological and clinical understanding of the alternatively-spliced TP53 isoforms. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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Review

Jump to: Research, Other

45 pages, 3130 KiB

Open AccessEditor’s ChoiceReview

Isoforms of the p53 Family and Gastric Cancer: A Ménage à Trois for an Unfinished Affair

by Anais Blanchet, Agathe Bourgmayer, Jean-Emmanuel Kurtz, Georg Mellitzer and Christian Gaiddon

Cancers 2021, 13(4), 916; https://doi.org/10.3390/cancers13040916 - 22 Feb 2021

Cited by 42 | Viewed by 6514

Abstract

Gastric cancer is one of the most aggressive cancers, with a median survival of 12 months. This illustrates its complexity and the lack of therapeutic options, such as personalized therapy, because predictive markers do not exist. Thus, gastric cancer remains mostly treated with [...] Read more.

Gastric cancer is one of the most aggressive cancers, with a median survival of 12 months. This illustrates its complexity and the lack of therapeutic options, such as personalized therapy, because predictive markers do not exist. Thus, gastric cancer remains mostly treated with cytotoxic chemotherapies. In addition, less than 20% of patients respond to immunotherapy. TP53 mutations are particularly frequent in gastric cancer (±50% and up to 70% in metastatic) and are considered an early event in the tumorigenic process. Alterations in the expression of other members of the p53 family, i.e., p63 and p73, have also been described. In this context, the role of the members of the p53 family and their isoforms have been investigated over the years, resulting in conflicting data. For instance, whether mutations of TP53 or the dysregulation of its homologs may represent biomarkers for aggressivity or response to therapy still remains a matter of debate. This uncertainty illustrates the lack of information on the molecular pathways involving the p53 family in gastric cancer. In this review, we summarize and discuss the most relevant molecular and clinical data on the role of the p53 family in gastric cancer and enumerate potential therapeutic innovative strategies. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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18 pages, 1540 KiB

Open AccessReview

Isoform-Specific Roles of Mutant p63 in Human Diseases

by Christian Osterburg, Susanne Osterburg, Huiqing Zhou, Caterina Missero and Volker Dötsch

Cancers 2021, 13(3), 536; https://doi.org/10.3390/cancers13030536 - 31 Jan 2021

Cited by 21 | Viewed by 4166

Abstract

The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the DNA binding domain cause Ectrodactyly, Ectodermal Dysplasia, characterized by limb deformation, cleft lip/palate, and ectodermal dysplasia while mutations in in the C-terminal domain of the α-isoform [...] Read more.

The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the DNA binding domain cause Ectrodactyly, Ectodermal Dysplasia, characterized by limb deformation, cleft lip/palate, and ectodermal dysplasia while mutations in in the C-terminal domain of the α-isoform cause Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility, severe, long-lasting skin erosions, and cleft lip/palate. The molecular disease mechanisms of these syndromes have recently become elucidated and have enhanced our understanding of the role of p63 in epidermal development. Here we review the molecular cause and functional consequences of these p63-mutations for skin development and discuss the consequences of p63 mutations for female fertility. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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15 pages, 1116 KiB

Open AccessReview

p53, A Victim of the Prion Fashion

by Olivier Billant, Gaëlle Friocourt, Pierre Roux and Cécile Voisset

Cancers 2021, 13(2), 269; https://doi.org/10.3390/cancers13020269 - 13 Jan 2021

Cited by 12 | Viewed by 4499

Abstract

Identified in the late 1970s as an oncogene, a driving force leading to tumor development, p53 turned out to be a key tumor suppressor gene. Now p53 is considered a master gene regulating the transcription of over 3000 target genes and controlling a [...] Read more.

Identified in the late 1970s as an oncogene, a driving force leading to tumor development, p53 turned out to be a key tumor suppressor gene. Now p53 is considered a master gene regulating the transcription of over 3000 target genes and controlling a remarkable number of cellular functions. The elevated prevalence of p53 mutations in human cancers has led to a recurring questioning about the roles of mutant p53 proteins and their functional consequences. Both mutants and isoforms of p53 have been attributed dominant-negative and gain of function properties among which is the ability to form amyloid aggregates and behave in a prion-like manner. This report challenges the ongoing “prion p53” hypothesis by reviewing evidence of p53 behavior in light of our current knowledge regarding amyloid proteins, prionoids and prions. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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20 pages, 2110 KiB

Open AccessReview

The Δ133p53 Isoforms, Tuners of the p53 Pathway

by Sebastien M. Joruiz, Jessica A. Beck, Izumi Horikawa and Curtis C. Harris

Cancers 2020, 12(11), 3422; https://doi.org/10.3390/cancers12113422 - 18 Nov 2020

Cited by 26 | Viewed by 5726

Abstract

The TP53 gene is a critical tumor suppressor and key determinant of cell fate which regulates numerous cellular functions including DNA repair, cell cycle arrest, cellular senescence, apoptosis, autophagy and metabolism. In the last 15 years, the p53 pathway has grown in complexity [...] Read more.

The TP53 gene is a critical tumor suppressor and key determinant of cell fate which regulates numerous cellular functions including DNA repair, cell cycle arrest, cellular senescence, apoptosis, autophagy and metabolism. In the last 15 years, the p53 pathway has grown in complexity through the discovery that TP53 differentially expresses twelve p53 protein isoforms in human cells with both overlapping and unique biologic activities. Here, we summarize the current knowledge on the Δ133p53 isoforms (Δ133p53α, Δ133p53β and Δ133p53γ), which are evolutionary derived and found only in human and higher order primates. All three isoforms lack both of the transactivation domains and the beginning of the DNA-binding domain. Despite the absence of these canonical domains, the Δ133p53 isoforms maintain critical functions in cancer, physiological and premature aging, neurodegenerative diseases, immunity and inflammation, and tissue repair. The ability of the Δ133p53 isoforms to modulate the p53 pathway functions underscores the need to include these p53 isoforms in our understanding of how the p53 pathway contributes to multiple physiological and pathological mechanisms. Critically, further characterization of p53 isoforms may identify novel regulatory modes of p53 pathway functions that contribute to disease progression and facilitate the development of new therapeutic strategies. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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22 pages, 2242 KiB

Open AccessReview

Good Cop, Bad Cop: Defining the Roles of Δ40p53 in Cancer and Aging

by Luiza Steffens Reinhardt, Xiajie Zhang, Anna Wawruszak, Kira Groen, Geoffry N. De Iuliis and Kelly A. Avery-Kiejda

Cancers 2020, 12(6), 1659; https://doi.org/10.3390/cancers12061659 - 23 Jun 2020

Cited by 21 | Viewed by 5025

Abstract

The tumour suppressor p53 is essential for maintaining DNA integrity, and plays a major role in cellular senescence and aging. Understanding the mechanisms that contribute to p53 dysfunction can uncover novel possibilities for improving cancer therapies and diagnosis, as well as cognitive decline [...] Read more.

The tumour suppressor p53 is essential for maintaining DNA integrity, and plays a major role in cellular senescence and aging. Understanding the mechanisms that contribute to p53 dysfunction can uncover novel possibilities for improving cancer therapies and diagnosis, as well as cognitive decline associated with aging. In recent years, the complexity of p53 signalling has become increasingly apparent owing to the discovery of the p53 isoforms. These isoforms play important roles in regulating cell growth and turnover in response to different stressors, depending on the cellular context. In this review, we focus on Δ40p53, an N-terminally truncated p53 isoform. Δ40p53 can alter p53 target gene expression in both a positive and negative manner, modulating the biological outcome of p53 activation; it also functions independently of p53. Therefore, proper control of the Δ40p53: p53 ratio is essential for normal cell growth, aging, and responses to cancer therapy. Defining the contexts and the mechanisms by which Δ40p53 behaves as a “good cop or bad cop” is critical if we are to target this isoform therapeutically. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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Other

Jump to: Research, Review

11 pages, 2444 KiB

Open AccessBrief Report

DNA-Damage-Induced Alternative Splicing of p53

by Jing Chen, Dadong Zhang, Xiaodi Qin, Kouros Owzar, Jennifer J. McCann and Michael B. Kastan

Cancers 2021, 13(2), 251; https://doi.org/10.3390/cancers13020251 - 12 Jan 2021

Cited by 13 | Viewed by 4637

Abstract

Cellular responses to DNA damage and other stresses are important determinants of mutagenesis and impact the development of a wide range of human diseases. TP53 is highly mutated in human cancers and plays an essential role in stress responses and cell fate determination. [...] Read more.

Cellular responses to DNA damage and other stresses are important determinants of mutagenesis and impact the development of a wide range of human diseases. TP53 is highly mutated in human cancers and plays an essential role in stress responses and cell fate determination. A central dogma of p53 induction after DNA damage has been that the induction results from a transient increase in the half-life of the p53 protein. Our laboratory recently demonstrated that this long-standing paradigm is an incomplete picture of p53 regulation by uncovering a critical role for protein translational regulation in p53 induction after DNA damage. These investigations led to the discovery of a DNA-damage-induced alternative splicing (AS) pathway that affects p53 and other gene products. The damage-induced AS of p53 pre-mRNA generates the beta isoform of p53 (p53β) RNA and protein, which is specifically required for the induction of cellular senescence markers after ionizing irradiation (IR). In an attempt to elucidate the mechanisms behind the differential regulation and apparent functional divergence between full-length (FL) p53 and the p53β isoform (apoptosis versus senescence, respectively), we identified the differential transcriptome and protein interactome between these two proteins that may result from the unique 10-amino-acid tail in p53β protein. Full article

(This article belongs to the Special Issue The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop)

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The Isoforms of the p53 Gene Family and Their Role in Cancer and Aging：Selection Papers from International p53/p63/p73 Isoforms Workshop

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