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MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation
Stress-activated p38 kinases control a plethora of functions, and their dysregulation has been linked to the development of steatosis, obesity, immune disorders, and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381040/ https://www.ncbi.nlm.nih.gov/pubmed/35971771 http://dx.doi.org/10.7554/eLife.75250 |
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author | Romero-Becerra, Rafael Mora, Alfonso Manieri, Elisa Nikolic, Ivana Santamans, Ayelén Melina Montalvo-Romeral, Valle Cruz, Francisco Miguel Rodríguez, Elena León, Marta Leiva-Vega, Luis Sanz, Laura Bondía, Víctor Filgueiras-Rama, David Jiménez-Borreguero, Luis Jesús Jalife, José Gonzalez-Teran, Barbara Sabio, Guadalupe |
author_facet | Romero-Becerra, Rafael Mora, Alfonso Manieri, Elisa Nikolic, Ivana Santamans, Ayelén Melina Montalvo-Romeral, Valle Cruz, Francisco Miguel Rodríguez, Elena León, Marta Leiva-Vega, Luis Sanz, Laura Bondía, Víctor Filgueiras-Rama, David Jiménez-Borreguero, Luis Jesús Jalife, José Gonzalez-Teran, Barbara Sabio, Guadalupe |
author_sort | Romero-Becerra, Rafael |
collection | PubMed |
description | Stress-activated p38 kinases control a plethora of functions, and their dysregulation has been linked to the development of steatosis, obesity, immune disorders, and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38α, p38β, p38γ, and p38δ) that are activated by MKK3 and MKK6. Here, we demonstrate that lack of MKK6 reduces the lifespan in mice. Longitudinal study of cardiac function in MKK6 KO mice showed that young mice develop cardiac hypertrophy which progresses to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and increased mammalian target of rapamycin (mTOR) signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in MKK6 KO mice is reverted by knocking out either p38γ or p38δ or by inhibiting the mTOR pathway with rapamycin. In conclusion, we have identified a key role for the MKK3/6-p38γ/δ pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38α inhibitors in the long-term treatment since they might result in cardiotoxicity. |
format | Online Article Text |
id | pubmed-9381040 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-93810402022-08-17 MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation Romero-Becerra, Rafael Mora, Alfonso Manieri, Elisa Nikolic, Ivana Santamans, Ayelén Melina Montalvo-Romeral, Valle Cruz, Francisco Miguel Rodríguez, Elena León, Marta Leiva-Vega, Luis Sanz, Laura Bondía, Víctor Filgueiras-Rama, David Jiménez-Borreguero, Luis Jesús Jalife, José Gonzalez-Teran, Barbara Sabio, Guadalupe eLife Cell Biology Stress-activated p38 kinases control a plethora of functions, and their dysregulation has been linked to the development of steatosis, obesity, immune disorders, and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38α, p38β, p38γ, and p38δ) that are activated by MKK3 and MKK6. Here, we demonstrate that lack of MKK6 reduces the lifespan in mice. Longitudinal study of cardiac function in MKK6 KO mice showed that young mice develop cardiac hypertrophy which progresses to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and increased mammalian target of rapamycin (mTOR) signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in MKK6 KO mice is reverted by knocking out either p38γ or p38δ or by inhibiting the mTOR pathway with rapamycin. In conclusion, we have identified a key role for the MKK3/6-p38γ/δ pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38α inhibitors in the long-term treatment since they might result in cardiotoxicity. eLife Sciences Publications, Ltd 2022-08-16 /pmc/articles/PMC9381040/ /pubmed/35971771 http://dx.doi.org/10.7554/eLife.75250 Text en © 2022, Romero-Becerra et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Romero-Becerra, Rafael Mora, Alfonso Manieri, Elisa Nikolic, Ivana Santamans, Ayelén Melina Montalvo-Romeral, Valle Cruz, Francisco Miguel Rodríguez, Elena León, Marta Leiva-Vega, Luis Sanz, Laura Bondía, Víctor Filgueiras-Rama, David Jiménez-Borreguero, Luis Jesús Jalife, José Gonzalez-Teran, Barbara Sabio, Guadalupe MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation |
title | MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation |
title_full | MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation |
title_fullStr | MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation |
title_full_unstemmed | MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation |
title_short | MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation |
title_sort | mkk6 deficiency promotes cardiac dysfunction through mkk3-p38γ/δ-mtor hyperactivation |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9381040/ https://www.ncbi.nlm.nih.gov/pubmed/35971771 http://dx.doi.org/10.7554/eLife.75250 |
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