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Limited Proteolysis of Cyclooxygenase-2 Enhances Cell Proliferation

Accumulating evidence suggests that the cyclooxygenase-2 (COX-2) enzyme has additional catalytic-independent functions. Here we show that COX-2 appears to be cleaved in mouse and human tumors, which led us to hypothesize that COX-2 proteolysis may play a role in cell proliferation. The data presente...

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Autores principales: Saadi, Esraa, Sood, Rapita, Dromi, Ido, Srouji, Ranin, Abu Hatoum, Ossama, Tal, Sharon, Barki-Harrington, Liza
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246915/
https://www.ncbi.nlm.nih.gov/pubmed/32366045
http://dx.doi.org/10.3390/ijms21093195
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author Saadi, Esraa
Sood, Rapita
Dromi, Ido
Srouji, Ranin
Abu Hatoum, Ossama
Tal, Sharon
Barki-Harrington, Liza
author_facet Saadi, Esraa
Sood, Rapita
Dromi, Ido
Srouji, Ranin
Abu Hatoum, Ossama
Tal, Sharon
Barki-Harrington, Liza
author_sort Saadi, Esraa
collection PubMed
description Accumulating evidence suggests that the cyclooxygenase-2 (COX-2) enzyme has additional catalytic-independent functions. Here we show that COX-2 appears to be cleaved in mouse and human tumors, which led us to hypothesize that COX-2 proteolysis may play a role in cell proliferation. The data presented herein show that a K598R point mutation at the carboxyl-terminus of COX-2 causes the appearance of several COX-2 immunoreactive fragments in nuclear compartments, and significantly enhances cell proliferation. In contrast, insertion of additional mutations at the border of the membrane-binding and catalytic domains of K598R COX-2 blocks fragment formation and prevents the increase in proliferation. Transcriptomic analyses show that K598R COX-2 significantly affects the expression of genes involved in RNA metabolism, and subsequent proteomics suggest that it is associated with proteins that regulate mRNA processing. We observe a similar increase in proliferation by expressing just that catalytic domain of COX-2 (ΔNT- COX-2), which is completely devoid of catalytic activity in the absence of its other domains. Moreover, we show that the ΔNT- COX-2 protein also interacts in the nucleus with β-catenin, a central regulator of gene transcription. Together these data suggest that the cleavage products of COX-2 can affect cell proliferation by mechanisms that are independent of prostaglandin synthesis.
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spelling pubmed-72469152020-06-02 Limited Proteolysis of Cyclooxygenase-2 Enhances Cell Proliferation Saadi, Esraa Sood, Rapita Dromi, Ido Srouji, Ranin Abu Hatoum, Ossama Tal, Sharon Barki-Harrington, Liza Int J Mol Sci Article Accumulating evidence suggests that the cyclooxygenase-2 (COX-2) enzyme has additional catalytic-independent functions. Here we show that COX-2 appears to be cleaved in mouse and human tumors, which led us to hypothesize that COX-2 proteolysis may play a role in cell proliferation. The data presented herein show that a K598R point mutation at the carboxyl-terminus of COX-2 causes the appearance of several COX-2 immunoreactive fragments in nuclear compartments, and significantly enhances cell proliferation. In contrast, insertion of additional mutations at the border of the membrane-binding and catalytic domains of K598R COX-2 blocks fragment formation and prevents the increase in proliferation. Transcriptomic analyses show that K598R COX-2 significantly affects the expression of genes involved in RNA metabolism, and subsequent proteomics suggest that it is associated with proteins that regulate mRNA processing. We observe a similar increase in proliferation by expressing just that catalytic domain of COX-2 (ΔNT- COX-2), which is completely devoid of catalytic activity in the absence of its other domains. Moreover, we show that the ΔNT- COX-2 protein also interacts in the nucleus with β-catenin, a central regulator of gene transcription. Together these data suggest that the cleavage products of COX-2 can affect cell proliferation by mechanisms that are independent of prostaglandin synthesis. MDPI 2020-04-30 /pmc/articles/PMC7246915/ /pubmed/32366045 http://dx.doi.org/10.3390/ijms21093195 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Saadi, Esraa
Sood, Rapita
Dromi, Ido
Srouji, Ranin
Abu Hatoum, Ossama
Tal, Sharon
Barki-Harrington, Liza
Limited Proteolysis of Cyclooxygenase-2 Enhances Cell Proliferation
title Limited Proteolysis of Cyclooxygenase-2 Enhances Cell Proliferation
title_full Limited Proteolysis of Cyclooxygenase-2 Enhances Cell Proliferation
title_fullStr Limited Proteolysis of Cyclooxygenase-2 Enhances Cell Proliferation
title_full_unstemmed Limited Proteolysis of Cyclooxygenase-2 Enhances Cell Proliferation
title_short Limited Proteolysis of Cyclooxygenase-2 Enhances Cell Proliferation
title_sort limited proteolysis of cyclooxygenase-2 enhances cell proliferation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246915/
https://www.ncbi.nlm.nih.gov/pubmed/32366045
http://dx.doi.org/10.3390/ijms21093195
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