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Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G(0)/G(1) Arrest by Inhibiting Deubiquitinase USP2a

USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent...

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Autores principales: Magiera, Katarzyna, Tomala, Marcin, Kubica, Katarzyna, De Cesare, Virginia, Trost, Matthias, Zieba, Bartosz J., Kachamakova-Trojanowska, Neli, Les, Marcin, Dubin, Grzegorz, Holak, Tad A., Skalniak, Lukasz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404848/
https://www.ncbi.nlm.nih.gov/pubmed/28343940
http://dx.doi.org/10.1016/j.chembiol.2017.03.002
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author Magiera, Katarzyna
Tomala, Marcin
Kubica, Katarzyna
De Cesare, Virginia
Trost, Matthias
Zieba, Bartosz J.
Kachamakova-Trojanowska, Neli
Les, Marcin
Dubin, Grzegorz
Holak, Tad A.
Skalniak, Lukasz
author_facet Magiera, Katarzyna
Tomala, Marcin
Kubica, Katarzyna
De Cesare, Virginia
Trost, Matthias
Zieba, Bartosz J.
Kachamakova-Trojanowska, Neli
Les, Marcin
Dubin, Grzegorz
Holak, Tad A.
Skalniak, Lukasz
author_sort Magiera, Katarzyna
collection PubMed
description USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCA hydroxyamide (LCAHA), inhibits USP2a, leading to a significant Akt/GSK3β-independent destabilization of cyclin D1, but does not change the expression of p27. This leads to the defects in cell-cycle progression. As a result, LCAHA inhibits the growth of cyclin D1-expressing, but not cyclin D1-negative cells, independently of the p53 status. We show that LCA derivatives may be considered as future therapeutics for the treatment of cyclin D1-addicted p53-expressing and p53-defective cancer types.
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spelling pubmed-54048482017-05-05 Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G(0)/G(1) Arrest by Inhibiting Deubiquitinase USP2a Magiera, Katarzyna Tomala, Marcin Kubica, Katarzyna De Cesare, Virginia Trost, Matthias Zieba, Bartosz J. Kachamakova-Trojanowska, Neli Les, Marcin Dubin, Grzegorz Holak, Tad A. Skalniak, Lukasz Cell Chem Biol Article USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCA hydroxyamide (LCAHA), inhibits USP2a, leading to a significant Akt/GSK3β-independent destabilization of cyclin D1, but does not change the expression of p27. This leads to the defects in cell-cycle progression. As a result, LCAHA inhibits the growth of cyclin D1-expressing, but not cyclin D1-negative cells, independently of the p53 status. We show that LCA derivatives may be considered as future therapeutics for the treatment of cyclin D1-addicted p53-expressing and p53-defective cancer types. Cell Press 2017-04-20 /pmc/articles/PMC5404848/ /pubmed/28343940 http://dx.doi.org/10.1016/j.chembiol.2017.03.002 Text en © 2017 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Magiera, Katarzyna
Tomala, Marcin
Kubica, Katarzyna
De Cesare, Virginia
Trost, Matthias
Zieba, Bartosz J.
Kachamakova-Trojanowska, Neli
Les, Marcin
Dubin, Grzegorz
Holak, Tad A.
Skalniak, Lukasz
Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G(0)/G(1) Arrest by Inhibiting Deubiquitinase USP2a
title Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G(0)/G(1) Arrest by Inhibiting Deubiquitinase USP2a
title_full Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G(0)/G(1) Arrest by Inhibiting Deubiquitinase USP2a
title_fullStr Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G(0)/G(1) Arrest by Inhibiting Deubiquitinase USP2a
title_full_unstemmed Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G(0)/G(1) Arrest by Inhibiting Deubiquitinase USP2a
title_short Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G(0)/G(1) Arrest by Inhibiting Deubiquitinase USP2a
title_sort lithocholic acid hydroxyamide destabilizes cyclin d1 and induces g(0)/g(1) arrest by inhibiting deubiquitinase usp2a
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404848/
https://www.ncbi.nlm.nih.gov/pubmed/28343940
http://dx.doi.org/10.1016/j.chembiol.2017.03.002
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