Cancers

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6 pages, 804 KiB

Open AccessEditorial

The Role of p53 Family in Cancer

by Joanna E. Zawacka-Pankau

Cancers 2022, 14(3), 823; https://doi.org/10.3390/cancers14030823 - 6 Feb 2022

Cited by 18 | Viewed by 2272

Abstract

This Special Issue covers a broad topic on the role of the p53 protein family in cancer [...] Full article

(This article belongs to the Special Issue The Role of p53 Family in Cancer)

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Review

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14 pages, 1684 KiB

Open AccessReview

The p53 Family Members p63 and p73 Roles in the Metastatic Dissemination: Interactions with microRNAs and TGFβ Pathway

by Lidia Rodriguez Calleja, Melanie Lavaud, Robel Tesfaye, Bénédicte Brounais-Le-Royer, Marc Baud’huin, Steven Georges, François Lamoureux, Franck Verrecchia and Benjamin Ory

Cancers 2022, 14(23), 5948; https://doi.org/10.3390/cancers14235948 - 1 Dec 2022

Cited by 6 | Viewed by 2138

Abstract

TP53 (TP53), p73 (TP73), and p63 (TP63) are members of the p53 transcription factor family, which has many activities spanning from embryonic development through to tumor suppression. The utilization of two promoters and alternative mRNA splicing has been shown to yield numerous isoforms [...] Read more.

TP53 (TP53), p73 (TP73), and p63 (TP63) are members of the p53 transcription factor family, which has many activities spanning from embryonic development through to tumor suppression. The utilization of two promoters and alternative mRNA splicing has been shown to yield numerous isoforms in p53, p63, and p73. TAp73 is thought to mediate apoptosis as a result of nuclear accumulation following chemotherapy-induced DNA damage, according to a number of studies. Overexpression of the nuclear ΔNp63 and ΔNp73 isoforms, on the other hand, suppresses TAp73’s pro-apoptotic activity in human malignancies, potentially leading to metastatic spread or inhibition. Another well-known pathway that has been associated to metastatic spread is the TGF pathway. TGFs are a family of structurally related polypeptide growth factors that regulate a variety of cellular functions including cell proliferation, lineage determination, differentiation, motility, adhesion, and cell death, making them significant players in development, homeostasis, and wound repair. Various studies have already identified several interactions between the p53 protein family and the TGFb pathway in the context of tumor growth and metastatic spread, beginning to shed light on this enigmatic intricacy. Full article

(This article belongs to the Special Issue The Role of p53 Family in Cancer)

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15 pages, 1009 KiB

Open AccessReview

The Underestimated Role of the p53 Pathway in Renal Cancer

by Alessandra Amendolare, Flaviana Marzano, Vittoria Petruzzella, Rosa Anna Vacca, Luisa Guerrini, Graziano Pesole, Elisabetta Sbisà and Apollonia Tullo

Cancers 2022, 14(23), 5733; https://doi.org/10.3390/cancers14235733 - 22 Nov 2022

Cited by 5 | Viewed by 1984

Abstract

The TP53 tumor suppressor gene is known as the guardian of the genome, playing a pivotal role in controlling genome integrity, and its functions are lost in more than 50% of human tumors due to somatic mutations. This percentage rises to 90% if [...] Read more.

The TP53 tumor suppressor gene is known as the guardian of the genome, playing a pivotal role in controlling genome integrity, and its functions are lost in more than 50% of human tumors due to somatic mutations. This percentage rises to 90% if mutations and alterations in the genes that code for regulators of p53 stability and activity are taken into account. Renal cell carcinoma (RCC) is a clear example of cancer that despite having a wild-type p53 shows poor prognosis because of the high rate of resistance to radiotherapy or chemotherapy, which leads to recurrence, metastasis and death. Remarkably, the fact that p53 is poorly mutated does not mean that it is functionally active, and increasing experimental evidences have demonstrated this. Therefore, RCC represents an extraordinary example of the importance of p53 pathway alterations in therapy resistance. The search for novel molecular biomarkers involved in the pathways that regulate altered p53 in RCC is mandatory for improving early diagnosis, evaluating the prognosis and developing novel potential therapeutic targets for better RCC treatment. Full article

(This article belongs to the Special Issue The Role of p53 Family in Cancer)

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21 pages, 1784 KiB

Open AccessReview

Inhibiting the Priming for Cancer in Li-Fraumeni Syndrome

by Pan Pantziarka and Sarah Blagden

Cancers 2022, 14(7), 1621; https://doi.org/10.3390/cancers14071621 - 23 Mar 2022

Cited by 3 | Viewed by 5891

Abstract

The concept of the pre-cancerous niche applies the ‘seed and soil’ theory of metastasis to the initial process of carcinogenesis. TP53 is at the nexus of this process and, in the context of Li-Fraumeni Syndrome (LFS), is a key determinant of the conditions [...] Read more.

The concept of the pre-cancerous niche applies the ‘seed and soil’ theory of metastasis to the initial process of carcinogenesis. TP53 is at the nexus of this process and, in the context of Li-Fraumeni Syndrome (LFS), is a key determinant of the conditions in which cancers are formed and progress. Important factors in the creation of the pre-cancerous niche include disrupted tissue homeostasis, cellular metabolism and chronic inflammation. While druggability of TP53 remains a challenge, there is evidence that drug re-purposing may be able to address aspects of pre-cancerous niche formation and thereby reduce the risk of cancer in individuals with LFS. Full article

(This article belongs to the Special Issue The Role of p53 Family in Cancer)

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23 pages, 2651 KiB

Open AccessReview

The Role of p53 in Progression of Cutaneous Squamous Cell Carcinoma

by Minna Piipponen, Pilvi Riihilä, Liisa Nissinen and Veli-Matti Kähäri

Cancers 2021, 13(18), 4507; https://doi.org/10.3390/cancers13184507 - 7 Sep 2021

Cited by 28 | Viewed by 4639

Abstract

Skin cancers are the most common types of cancer worldwide, and their incidence is increasing. Melanoma, basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (cSCC) are the three major types of skin cancer. Melanoma originates from melanocytes, whereas BCC and cSCC originate [...] Read more.

Skin cancers are the most common types of cancer worldwide, and their incidence is increasing. Melanoma, basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (cSCC) are the three major types of skin cancer. Melanoma originates from melanocytes, whereas BCC and cSCC originate from epidermal keratinocytes and are therefore called keratinocyte carcinomas. Chronic exposure to ultraviolet radiation (UVR) is a common risk factor for skin cancers, but they differ with respect to oncogenic mutational profiles and alterations in cellular signaling pathways. cSCC is the most common metastatic skin cancer, and it is associated with poor prognosis in the advanced stage. An important early event in cSCC development is mutation of the TP53 gene and inactivation of the tumor suppressor function of the tumor protein 53 gene (TP53) in epidermal keratinocytes, which then leads to accumulation of additional oncogenic mutations. Additional genomic and proteomic alterations are required for the progression of premalignant lesion, actinic keratosis, to invasive and metastatic cSCC. Recently, the role of p53 in the invasion of cSCC has also been elucidated. In this review, the role of p53 in the progression of cSCC and as potential new therapeutic target for cSCC will be discussed. Full article

(This article belongs to the Special Issue The Role of p53 Family in Cancer)

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19 pages, 722 KiB

Open AccessReview

The Function of the Mutant p53-R175H in Cancer

by Yen-Ting Chiang, Yi-Chung Chien, Yu-Heng Lin, Hui-Hsuan Wu, Dung-Fang Lee and Yung-Luen Yu

Cancers 2021, 13(16), 4088; https://doi.org/10.3390/cancers13164088 - 13 Aug 2021

Cited by 35 | Viewed by 6432

Abstract

Wild-type p53 is known as “the guardian of the genome” because of its function of inducing DNA repair, cell-cycle arrest, and apoptosis, preventing the accumulation of gene mutations. TP53 is highly mutated in cancer cells and most TP53 hotspot mutations are missense mutations. [...] Read more.

Wild-type p53 is known as “the guardian of the genome” because of its function of inducing DNA repair, cell-cycle arrest, and apoptosis, preventing the accumulation of gene mutations. TP53 is highly mutated in cancer cells and most TP53 hotspot mutations are missense mutations. Mutant p53 proteins, encoded by these hotspot mutations, lose canonical wild-type p53 functions and gain functions that promote cancer development, including promoting cancer cell proliferation, migration, invasion, initiation, metabolic reprogramming, angiogenesis, and conferring drug resistance to cancer cells. Among these hotspot mutations, p53-R175H has the highest occurrence. Although losing the transactivating function of the wild-type p53 and prone to aggregation, p53-R175H gains oncogenic functions by interacting with many proteins. In this review, we summarize the gain of functions of p53-R175H in different cancer types, the interacting proteins of p53-R175H, and the downstream signaling pathways affected by p53-R175H to depict a comprehensive role of p53-R175H in cancer development. We also summarize treatments that target p53-R175H, including reactivating p53-R175H with small molecules that can bind to p53-R175H and alter it into a wild-type-like structure, promoting the degradation of p53-R175H by targeting heat-shock proteins that maintain the stability of p53-R175H, and developing immunotherapies that target the p53-R175H–HLA complex presented by tumor cells. Full article

(This article belongs to the Special Issue The Role of p53 Family in Cancer)

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22 pages, 3204 KiB

Open AccessFeature PaperReview

The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy-Drug Repurposing

by Joanna E. Zawacka-Pankau

Cancers 2020, 12(9), 2717; https://doi.org/10.3390/cancers12092717 - 22 Sep 2020

Cited by 8 | Viewed by 5108

Abstract

p53 and p73 are critical tumor suppressors that are often inactivated in human cancers through various mechanisms. Owing to their high structural homology, the proteins have many joined functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. [...] Read more.

p53 and p73 are critical tumor suppressors that are often inactivated in human cancers through various mechanisms. Owing to their high structural homology, the proteins have many joined functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the ‘guardian of the genome’ and together with p73 forms a barrier against cancer development and progression. The TP53 is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li–Fraumeni syndrome (LFS), the inherited cancer predisposition. In cancers where TP53 gene is intact, p53 is degraded. Despite the ongoing efforts, the treatment of cancers remains challenging. This is due to late diagnoses, the toxicity of the current standard of care and marginal benefit of newly approved therapies. Presently, the endeavors focus on reactivating p53 exclusively, neglecting the potential of the restoration of p73 protein for cancer eradication. Taken that several small molecules reactivating p53 failed in clinical trials, there is a need to develop new treatments targeting p53 proteins in cancer. This review outlines the most advanced strategies to reactivate p53 and p73 and describes drug repurposing approaches for the efficient reinstatement of the p53 proteins for cancer therapy. Full article

(This article belongs to the Special Issue The Role of p53 Family in Cancer)

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Other

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12 pages, 935 KiB

Open AccessPerspective

Early TP53 Alterations Shape Gastric and Esophageal Cancer Development

by Pranshu Sahgal, Brandon M. Huffman, Deepa T. Patil, Walid K. Chatila, Rona Yaeger, James M. Cleary and Nilay S. Sethi

Cancers 2021, 13(23), 5915; https://doi.org/10.3390/cancers13235915 - 24 Nov 2021

Cited by 8 | Viewed by 3119

Abstract

Gastric and esophageal (GE) adenocarcinomas are the third and sixth most common causes of cancer-related mortality worldwide, accounting for greater than 1.25 million annual deaths. Despite the advancements in the multi-disciplinary treatment approaches, the prognosis for patients with GE adenocarcinomas remains poor, with [...] Read more.

Gastric and esophageal (GE) adenocarcinomas are the third and sixth most common causes of cancer-related mortality worldwide, accounting for greater than 1.25 million annual deaths. Despite the advancements in the multi-disciplinary treatment approaches, the prognosis for patients with GE adenocarcinomas remains poor, with a 5-year survival of 32% and 19%, respectively, mainly due to the late-stage diagnosis and aggressive nature of these cancers. Premalignant lesions characterized by atypical glandular proliferation, with neoplastic cells confined to the basement membrane, often precede malignant disease. We now appreciate that premalignant lesions also carry cancer-associated mutations, enabling disease progression in the right environmental context. A better understanding of the premalignant-to-malignant transition can help us diagnose, prevent, and treat GE adenocarcinoma. Here, we discuss the evidence suggesting that alterations in TP53 occur early in GE adenocarcinoma evolution, are selected for under environmental stressors, are responsible for shaping the genomic mechanisms for pathway dysregulation in cancer progression, and lead to potential vulnerabilities that can be exploited by a specific class of targeted therapy. Full article

(This article belongs to the Special Issue The Role of p53 Family in Cancer)

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11 pages, 1153 KiB

Open AccessCommentary

p53-Dependent Repression: DREAM or Reality?

by Sylvain Peuget and Galina Selivanova

Cancers 2021, 13(19), 4850; https://doi.org/10.3390/cancers13194850 - 28 Sep 2021

Cited by 13 | Viewed by 2539

Abstract

p53 is a major tumor suppressor that integrates diverse types of signaling in mammalian cells. In response to a broad range of intra- or extra-cellular stimuli, p53 controls the expression of multiple target genes and elicits a vast repertoire of biological responses. The [...] Read more.

p53 is a major tumor suppressor that integrates diverse types of signaling in mammalian cells. In response to a broad range of intra- or extra-cellular stimuli, p53 controls the expression of multiple target genes and elicits a vast repertoire of biological responses. The exact code by which p53 integrates the various stresses and translates them into an appropriate transcriptional response is still obscure. p53 is tightly regulated at multiple levels, leading to a wide diversity in p53 complexes on its target promoters and providing adaptability to its transcriptional program. As p53-targeted therapies are making their way into clinics, we need to understand how to direct p53 towards the desired outcome (i.e., cell death, senescence or other) selectively in cancer cells without affecting normal tissues or the immune system. While the core p53 transcriptional program has been proposed, the mechanisms conferring a cell type- and stimuli-dependent transcriptional outcome by p53 require further investigations. The mechanism by which p53 localizes to repressed promoters and manages its co-repressor interactions is controversial and remains an important gap in our understanding of the p53 cistrome. We hope that our review of the recent literature will help to stimulate the appreciation and investigation of largely unexplored p53-mediated repression. Full article

(This article belongs to the Special Issue The Role of p53 Family in Cancer)

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