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...
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Autor*in:	Rafael Romero-Becerra [verfasserIn] Alfonso Mora [verfasserIn] Elisa Manieri [verfasserIn] Ivana Nikolic [verfasserIn] Ayelén Melina Santamans [verfasserIn] Valle Montalvo-Romeral [verfasserIn] Francisco Miguel Cruz [verfasserIn] Elena Rodríguez [verfasserIn] Marta León [verfasserIn] Luis Leiva-Vega [verfasserIn] Laura Sanz [verfasserIn] Víctor Bondía [verfasserIn] David Filgueiras-Rama [verfasserIn] Luis Jesús Jiménez-Borreguero [verfasserIn] José Jalife [verfasserIn] Barbara Gonzalez-Teran [verfasserIn] Guadalupe Sabio [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	p38 MAPK cardiac hypertrophy MKK6 MKK3 mTOR aging

Übergeordnetes Werk:	In: eLife - eLife Sciences Publications Ltd, 2013, 11(2022)
Übergeordnetes Werk:	volume:11 ; year:2022

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.7554/eLife.75250

Katalog-ID:	DOAJ084568771

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allfields	10.7554/eLife.75250 doi (DE-627)DOAJ084568771 (DE-599)DOAJ5fb94dd9292040efb96bdc1f5880f2fb DE-627 ger DE-627 rakwb eng QH301-705.5 Rafael Romero-Becerra verfasserin aut MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. p38 MAPK cardiac hypertrophy MKK6 MKK3 mTOR aging Medicine R Science Q Biology (General) Alfonso Mora verfasserin aut Elisa Manieri verfasserin aut Ivana Nikolic verfasserin aut Ayelén Melina Santamans verfasserin aut Valle Montalvo-Romeral verfasserin aut Francisco Miguel Cruz verfasserin aut Elena Rodríguez verfasserin aut Marta León verfasserin aut Luis Leiva-Vega verfasserin aut Laura Sanz verfasserin aut Víctor Bondía verfasserin aut David Filgueiras-Rama verfasserin aut Luis Jesús Jiménez-Borreguero verfasserin aut José Jalife verfasserin aut Barbara Gonzalez-Teran verfasserin aut Guadalupe Sabio verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 11(2022) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:11 year:2022 https://doi.org/10.7554/eLife.75250 kostenfrei https://doaj.org/article/5fb94dd9292040efb96bdc1f5880f2fb kostenfrei https://elifesciences.org/articles/75250 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022
spelling	10.7554/eLife.75250 doi (DE-627)DOAJ084568771 (DE-599)DOAJ5fb94dd9292040efb96bdc1f5880f2fb DE-627 ger DE-627 rakwb eng QH301-705.5 Rafael Romero-Becerra verfasserin aut MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. p38 MAPK cardiac hypertrophy MKK6 MKK3 mTOR aging Medicine R Science Q Biology (General) Alfonso Mora verfasserin aut Elisa Manieri verfasserin aut Ivana Nikolic verfasserin aut Ayelén Melina Santamans verfasserin aut Valle Montalvo-Romeral verfasserin aut Francisco Miguel Cruz verfasserin aut Elena Rodríguez verfasserin aut Marta León verfasserin aut Luis Leiva-Vega verfasserin aut Laura Sanz verfasserin aut Víctor Bondía verfasserin aut David Filgueiras-Rama verfasserin aut Luis Jesús Jiménez-Borreguero verfasserin aut José Jalife verfasserin aut Barbara Gonzalez-Teran verfasserin aut Guadalupe Sabio verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 11(2022) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:11 year:2022 https://doi.org/10.7554/eLife.75250 kostenfrei https://doaj.org/article/5fb94dd9292040efb96bdc1f5880f2fb kostenfrei https://elifesciences.org/articles/75250 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022
allfields_unstemmed	10.7554/eLife.75250 doi (DE-627)DOAJ084568771 (DE-599)DOAJ5fb94dd9292040efb96bdc1f5880f2fb DE-627 ger DE-627 rakwb eng QH301-705.5 Rafael Romero-Becerra verfasserin aut MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. p38 MAPK cardiac hypertrophy MKK6 MKK3 mTOR aging Medicine R Science Q Biology (General) Alfonso Mora verfasserin aut Elisa Manieri verfasserin aut Ivana Nikolic verfasserin aut Ayelén Melina Santamans verfasserin aut Valle Montalvo-Romeral verfasserin aut Francisco Miguel Cruz verfasserin aut Elena Rodríguez verfasserin aut Marta León verfasserin aut Luis Leiva-Vega verfasserin aut Laura Sanz verfasserin aut Víctor Bondía verfasserin aut David Filgueiras-Rama verfasserin aut Luis Jesús Jiménez-Borreguero verfasserin aut José Jalife verfasserin aut Barbara Gonzalez-Teran verfasserin aut Guadalupe Sabio verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 11(2022) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:11 year:2022 https://doi.org/10.7554/eLife.75250 kostenfrei https://doaj.org/article/5fb94dd9292040efb96bdc1f5880f2fb kostenfrei https://elifesciences.org/articles/75250 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022
allfieldsGer	10.7554/eLife.75250 doi (DE-627)DOAJ084568771 (DE-599)DOAJ5fb94dd9292040efb96bdc1f5880f2fb DE-627 ger DE-627 rakwb eng QH301-705.5 Rafael Romero-Becerra verfasserin aut MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. p38 MAPK cardiac hypertrophy MKK6 MKK3 mTOR aging Medicine R Science Q Biology (General) Alfonso Mora verfasserin aut Elisa Manieri verfasserin aut Ivana Nikolic verfasserin aut Ayelén Melina Santamans verfasserin aut Valle Montalvo-Romeral verfasserin aut Francisco Miguel Cruz verfasserin aut Elena Rodríguez verfasserin aut Marta León verfasserin aut Luis Leiva-Vega verfasserin aut Laura Sanz verfasserin aut Víctor Bondía verfasserin aut David Filgueiras-Rama verfasserin aut Luis Jesús Jiménez-Borreguero verfasserin aut José Jalife verfasserin aut Barbara Gonzalez-Teran verfasserin aut Guadalupe Sabio verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 11(2022) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:11 year:2022 https://doi.org/10.7554/eLife.75250 kostenfrei https://doaj.org/article/5fb94dd9292040efb96bdc1f5880f2fb kostenfrei https://elifesciences.org/articles/75250 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022
allfieldsSound	10.7554/eLife.75250 doi (DE-627)DOAJ084568771 (DE-599)DOAJ5fb94dd9292040efb96bdc1f5880f2fb DE-627 ger DE-627 rakwb eng QH301-705.5 Rafael Romero-Becerra verfasserin aut MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. p38 MAPK cardiac hypertrophy MKK6 MKK3 mTOR aging Medicine R Science Q Biology (General) Alfonso Mora verfasserin aut Elisa Manieri verfasserin aut Ivana Nikolic verfasserin aut Ayelén Melina Santamans verfasserin aut Valle Montalvo-Romeral verfasserin aut Francisco Miguel Cruz verfasserin aut Elena Rodríguez verfasserin aut Marta León verfasserin aut Luis Leiva-Vega verfasserin aut Laura Sanz verfasserin aut Víctor Bondía verfasserin aut David Filgueiras-Rama verfasserin aut Luis Jesús Jiménez-Borreguero verfasserin aut José Jalife verfasserin aut Barbara Gonzalez-Teran verfasserin aut Guadalupe Sabio verfasserin aut In eLife eLife Sciences Publications Ltd, 2013 11(2022) (DE-627)728518384 (DE-600)2687154-3 2050084X nnns volume:11 year:2022 https://doi.org/10.7554/eLife.75250 kostenfrei https://doaj.org/article/5fb94dd9292040efb96bdc1f5880f2fb kostenfrei https://elifesciences.org/articles/75250 kostenfrei https://doaj.org/toc/2050-084X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2022
language	English
source	In eLife 11(2022) volume:11 year:2022
sourceStr	In eLife 11(2022) volume:11 year:2022
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topic_facet	p38 MAPK cardiac hypertrophy MKK6 MKK3 mTOR aging Medicine R Science Q Biology (General)
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container_title	eLife
authorswithroles_txt_mv	Rafael Romero-Becerra @@aut@@ Alfonso Mora @@aut@@ Elisa Manieri @@aut@@ Ivana Nikolic @@aut@@ Ayelén Melina Santamans @@aut@@ Valle Montalvo-Romeral @@aut@@ Francisco Miguel Cruz @@aut@@ Elena Rodríguez @@aut@@ Marta León @@aut@@ Luis Leiva-Vega @@aut@@ Laura Sanz @@aut@@ Víctor Bondía @@aut@@ David Filgueiras-Rama @@aut@@ Luis Jesús Jiménez-Borreguero @@aut@@ José Jalife @@aut@@ Barbara Gonzalez-Teran @@aut@@ Guadalupe Sabio @@aut@@
publishDateDaySort_date	2022-01-01T00:00:00Z
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callnumber-first	Q - Science
author	Rafael Romero-Becerra
spellingShingle	Rafael Romero-Becerra misc QH301-705.5 misc p38 MAPK misc cardiac hypertrophy misc MKK6 misc MKK3 misc mTOR misc aging misc Medicine misc R misc Science misc Q misc Biology (General) MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation
authorStr	Rafael Romero-Becerra
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topic_title	QH301-705.5 MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation p38 MAPK cardiac hypertrophy MKK6 MKK3 mTOR aging
topic	misc QH301-705.5 misc p38 MAPK misc cardiac hypertrophy misc MKK6 misc MKK3 misc mTOR misc aging misc Medicine misc R misc Science misc Q misc Biology (General)
topic_unstemmed	misc QH301-705.5 misc p38 MAPK misc cardiac hypertrophy misc MKK6 misc MKK3 misc mTOR misc aging misc Medicine misc R misc Science misc Q misc Biology (General)
topic_browse	misc QH301-705.5 misc p38 MAPK misc cardiac hypertrophy misc MKK6 misc MKK3 misc mTOR misc aging misc Medicine misc R misc Science misc Q misc Biology (General)
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title	MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation
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title_full	MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation
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author_browse	Rafael Romero-Becerra Alfonso Mora Elisa Manieri Ivana Nikolic Ayelén Melina Santamans Valle Montalvo-Romeral Francisco Miguel Cruz Elena Rodríguez Marta León Luis Leiva-Vega Laura Sanz Víctor Bondía David Filgueiras-Rama Luis Jesús Jiménez-Borreguero José Jalife Barbara Gonzalez-Teran Guadalupe Sabio
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title_sort	mkk6 deficiency promotes cardiac dysfunction through mkk3-p38γ/δ-mtor hyperactivation
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title_auth	MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation
url	https://doi.org/10.7554/eLife.75250 https://doaj.org/article/5fb94dd9292040efb96bdc1f5880f2fb https://elifesciences.org/articles/75250 https://doaj.org/toc/2050-084X
remote_bool	true
author2	Alfonso Mora Elisa Manieri Ivana Nikolic Ayelén Melina Santamans Valle Montalvo-Romeral Francisco Miguel Cruz Elena Rodríguez Marta León Luis Leiva-Vega Laura Sanz Víctor Bondía David Filgueiras-Rama Luis Jesús Jiménez-Borreguero José Jalife Barbara Gonzalez-Teran Guadalupe Sabio
author2Str	Alfonso Mora Elisa Manieri Ivana Nikolic Ayelén Melina Santamans Valle Montalvo-Romeral Francisco Miguel Cruz Elena Rodríguez Marta León Luis Leiva-Vega Laura Sanz Víctor Bondía David Filgueiras-Rama Luis Jesús Jiménez-Borreguero José Jalife Barbara Gonzalez-Teran Guadalupe Sabio
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isOA_txt	true
hochschulschrift_bool	false
doi_str	10.7554/eLife.75250
callnumber-a	QH301-705.5
up_date	2024-07-03T23:38:19.832Z
_version_	1803603043778822144
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