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Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases

New disease targets and medicinal chemistry approaches are urgently needed to develop novel therapeutic strategies for treating pulmonary diseases. Emerging evidence suggests that reduced activity of protein phosphatase 2A (PP2A), a complex heterotrimeric enzyme that regulates dephosphorylation of s...

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Autores principales: Yu, Howard, Zaveri, Sahil, Sattar, Zeeshan, Schaible, Michael, Perez Gandara, Brais, Uddin, Anwar, McGarvey, Lucas R., Ohlmeyer, Michael, Geraghty, Patrick
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10535831/
https://www.ncbi.nlm.nih.gov/pubmed/37763671
http://dx.doi.org/10.3390/medicina59091552
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author Yu, Howard
Zaveri, Sahil
Sattar, Zeeshan
Schaible, Michael
Perez Gandara, Brais
Uddin, Anwar
McGarvey, Lucas R.
Ohlmeyer, Michael
Geraghty, Patrick
author_facet Yu, Howard
Zaveri, Sahil
Sattar, Zeeshan
Schaible, Michael
Perez Gandara, Brais
Uddin, Anwar
McGarvey, Lucas R.
Ohlmeyer, Michael
Geraghty, Patrick
author_sort Yu, Howard
collection PubMed
description New disease targets and medicinal chemistry approaches are urgently needed to develop novel therapeutic strategies for treating pulmonary diseases. Emerging evidence suggests that reduced activity of protein phosphatase 2A (PP2A), a complex heterotrimeric enzyme that regulates dephosphorylation of serine and threonine residues from many proteins, is observed in multiple pulmonary diseases, including lung cancer, smoke-induced chronic obstructive pulmonary disease, alpha-1 antitrypsin deficiency, asthma, and idiopathic pulmonary fibrosis. Loss of PP2A responses is linked to many mechanisms associated with disease progressions, such as senescence, proliferation, inflammation, corticosteroid resistance, enhanced protease responses, and mRNA stability. Therefore, chemical restoration of PP2A may represent a novel treatment for these diseases. This review outlines the potential impact of reduced PP2A activity in pulmonary diseases, endogenous and exogenous inhibitors of PP2A, details the possible PP2A-dependent mechanisms observed in these conditions, and outlines potential therapeutic strategies for treatment. Substantial medicinal chemistry efforts are underway to develop therapeutics targeting PP2A activity. The development of specific activators of PP2A that selectively target PP2A holoenzymes could improve our understanding of the function of PP2A in pulmonary diseases. This may lead to the development of therapeutics for restoring normal PP2A responses within the lung.
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spelling pubmed-105358312023-09-29 Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases Yu, Howard Zaveri, Sahil Sattar, Zeeshan Schaible, Michael Perez Gandara, Brais Uddin, Anwar McGarvey, Lucas R. Ohlmeyer, Michael Geraghty, Patrick Medicina (Kaunas) Review New disease targets and medicinal chemistry approaches are urgently needed to develop novel therapeutic strategies for treating pulmonary diseases. Emerging evidence suggests that reduced activity of protein phosphatase 2A (PP2A), a complex heterotrimeric enzyme that regulates dephosphorylation of serine and threonine residues from many proteins, is observed in multiple pulmonary diseases, including lung cancer, smoke-induced chronic obstructive pulmonary disease, alpha-1 antitrypsin deficiency, asthma, and idiopathic pulmonary fibrosis. Loss of PP2A responses is linked to many mechanisms associated with disease progressions, such as senescence, proliferation, inflammation, corticosteroid resistance, enhanced protease responses, and mRNA stability. Therefore, chemical restoration of PP2A may represent a novel treatment for these diseases. This review outlines the potential impact of reduced PP2A activity in pulmonary diseases, endogenous and exogenous inhibitors of PP2A, details the possible PP2A-dependent mechanisms observed in these conditions, and outlines potential therapeutic strategies for treatment. Substantial medicinal chemistry efforts are underway to develop therapeutics targeting PP2A activity. The development of specific activators of PP2A that selectively target PP2A holoenzymes could improve our understanding of the function of PP2A in pulmonary diseases. This may lead to the development of therapeutics for restoring normal PP2A responses within the lung. MDPI 2023-08-26 /pmc/articles/PMC10535831/ /pubmed/37763671 http://dx.doi.org/10.3390/medicina59091552 Text en © 2023 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
Yu, Howard
Zaveri, Sahil
Sattar, Zeeshan
Schaible, Michael
Perez Gandara, Brais
Uddin, Anwar
McGarvey, Lucas R.
Ohlmeyer, Michael
Geraghty, Patrick
Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases
title Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases
title_full Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases
title_fullStr Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases
title_full_unstemmed Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases
title_short Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases
title_sort protein phosphatase 2a as a therapeutic target in pulmonary diseases
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10535831/
https://www.ncbi.nlm.nih.gov/pubmed/37763671
http://dx.doi.org/10.3390/medicina59091552
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