Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors

SIMPLE SUMMARY: The tumor suppressor TAp73 is a member of the p53 family, which is inhibited in many human solid and hematological tumors. In contrast to those in the p53 gene, mutations in the p73 gene are very rare in tumors, suggesting that the decrease in TAp73 activity and expression detected i...

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Autores principales: Omran, Ziad, H. Dalhat, Mahmood, Abdullah, Omeima, Kaleem, Mohammed, Hosawi, Salman, A Al-Abbasi, Fahd, Wu, Wei, Choudhry, Hani, Alhosin, Mahmoud
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071514/
https://www.ncbi.nlm.nih.gov/pubmed/33921128
http://dx.doi.org/10.3390/cancers13081916
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author Omran, Ziad
H. Dalhat, Mahmood
Abdullah, Omeima
Kaleem, Mohammed
Hosawi, Salman
A Al-Abbasi, Fahd
Wu, Wei
Choudhry, Hani
Alhosin, Mahmoud
author_facet Omran, Ziad
H. Dalhat, Mahmood
Abdullah, Omeima
Kaleem, Mohammed
Hosawi, Salman
A Al-Abbasi, Fahd
Wu, Wei
Choudhry, Hani
Alhosin, Mahmoud
author_sort Omran, Ziad
collection PubMed
description SIMPLE SUMMARY: The tumor suppressor TAp73 is a member of the p53 family, which is inhibited in many human solid and hematological tumors. In contrast to those in the p53 gene, mutations in the p73 gene are very rare in tumors, suggesting that the decrease in TAp73 activity and expression detected in those tumors are caused mainly by coordinated post-translational modifications of TAp73. Thus, understanding and investigating these post-translational modifications will allow for the identification of new targets to overcome the downregulation of TAp73 and, ultimately, the development of novel cancer therapeutics. This review highlights the multiple post-translational modifications underlying TAp73 regulation in cancer cells and the growing importance of targeting their trigger enzymes as a promising antitumor strategy. ABSTRACT: The tumor suppressor p73 is a member of the p53 family and is expressed as different isoforms with opposing properties. The TAp73 isoforms act as tumor suppressors and have pro-apoptotic effects, whereas the ΔNp73 isoforms lack the N-terminus transactivation domain and behave as oncogenes. The TAp73 protein has a high degree of similarity with both p53 function and structure, and it induces the regulation of various genes involved in the cell cycle and apoptosis. Unlike those of the p53 gene, the mutations in the p73 gene are very rare in tumors. Cancer cells have developed several mechanisms to inhibit the activity and/or expression of p73, from the hypermethylation of its promoter to the modulation of the ratio between its pro- and anti-apoptotic isoforms. The p73 protein is also decorated by a panel of post-translational modifications, including phosphorylation, acetylation, ubiquitin proteasomal pathway modifications, and small ubiquitin-related modifier (SUMO)ylation, that regulate its transcriptional activity, subcellular localization, and stability. These modifications orchestrate the multiple anti-proliferative and pro-apoptotic functions of TAp73, thereby offering multiple promising candidates for targeted anti-cancer therapies. In this review, we summarize the current knowledge of the different pathways implicated in the regulation of TAp73 at the post-translational level. This review also highlights the growing importance of targeting the post-translational modifications of TAp73 as a promising antitumor strategy, regardless of p53 status.
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spelling pubmed-80715142021-04-26 Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors Omran, Ziad H. Dalhat, Mahmood Abdullah, Omeima Kaleem, Mohammed Hosawi, Salman A Al-Abbasi, Fahd Wu, Wei Choudhry, Hani Alhosin, Mahmoud Cancers (Basel) Review SIMPLE SUMMARY: The tumor suppressor TAp73 is a member of the p53 family, which is inhibited in many human solid and hematological tumors. In contrast to those in the p53 gene, mutations in the p73 gene are very rare in tumors, suggesting that the decrease in TAp73 activity and expression detected in those tumors are caused mainly by coordinated post-translational modifications of TAp73. Thus, understanding and investigating these post-translational modifications will allow for the identification of new targets to overcome the downregulation of TAp73 and, ultimately, the development of novel cancer therapeutics. This review highlights the multiple post-translational modifications underlying TAp73 regulation in cancer cells and the growing importance of targeting their trigger enzymes as a promising antitumor strategy. ABSTRACT: The tumor suppressor p73 is a member of the p53 family and is expressed as different isoforms with opposing properties. The TAp73 isoforms act as tumor suppressors and have pro-apoptotic effects, whereas the ΔNp73 isoforms lack the N-terminus transactivation domain and behave as oncogenes. The TAp73 protein has a high degree of similarity with both p53 function and structure, and it induces the regulation of various genes involved in the cell cycle and apoptosis. Unlike those of the p53 gene, the mutations in the p73 gene are very rare in tumors. Cancer cells have developed several mechanisms to inhibit the activity and/or expression of p73, from the hypermethylation of its promoter to the modulation of the ratio between its pro- and anti-apoptotic isoforms. The p73 protein is also decorated by a panel of post-translational modifications, including phosphorylation, acetylation, ubiquitin proteasomal pathway modifications, and small ubiquitin-related modifier (SUMO)ylation, that regulate its transcriptional activity, subcellular localization, and stability. These modifications orchestrate the multiple anti-proliferative and pro-apoptotic functions of TAp73, thereby offering multiple promising candidates for targeted anti-cancer therapies. In this review, we summarize the current knowledge of the different pathways implicated in the regulation of TAp73 at the post-translational level. This review also highlights the growing importance of targeting the post-translational modifications of TAp73 as a promising antitumor strategy, regardless of p53 status. MDPI 2021-04-15 /pmc/articles/PMC8071514/ /pubmed/33921128 http://dx.doi.org/10.3390/cancers13081916 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Omran, Ziad
H. Dalhat, Mahmood
Abdullah, Omeima
Kaleem, Mohammed
Hosawi, Salman
A Al-Abbasi, Fahd
Wu, Wei
Choudhry, Hani
Alhosin, Mahmoud
Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors
title Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors
title_full Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors
title_fullStr Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors
title_full_unstemmed Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors
title_short Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors
title_sort targeting post-translational modifications of the p73 protein: a promising therapeutic strategy for tumors
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071514/
https://www.ncbi.nlm.nih.gov/pubmed/33921128
http://dx.doi.org/10.3390/cancers13081916
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