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CDK2 regulates aminoglycoside-induced hair cell death through modulating c-Jun activity: Inhibiting CDK2 to preserve hearing

Sensory hair cell death caused by the ototoxic side effects of many clinically used drugs leads to permanent sensorineural hearing loss in patients. Aminoglycoside antibiotics are widely used and well-known for their ototoxicity, but the molecular mechanisms of aminoglycoside-induced hair cell death...

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Autores principales: Tao, Litao, Segil, Neil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9606710/
https://www.ncbi.nlm.nih.gov/pubmed/36311033
http://dx.doi.org/10.3389/fnmol.2022.1013383
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author Tao, Litao
Segil, Neil
author_facet Tao, Litao
Segil, Neil
author_sort Tao, Litao
collection PubMed
description Sensory hair cell death caused by the ototoxic side effects of many clinically used drugs leads to permanent sensorineural hearing loss in patients. Aminoglycoside antibiotics are widely used and well-known for their ototoxicity, but the molecular mechanisms of aminoglycoside-induced hair cell death are not well understood. This creates challenges in our attempts to alleviate or prevent such adverse side effects. Here, we report a regulatory role of CDK2 in aminoglycoside-induced hair cell death. Utilizing organotypic cultures of cochleae from neonatal mice, we show that blocking CDK2 activity by either pharmaceutical inhibition or by Cdk2 gene knockout protects hair cells against the ototoxicity of gentamicin—one of the most commonly used aminoglycoside antibiotics—by interfering with intrinsic programmed cell death processes. Specifically, we show that CDK2 inhibition delays the collapse of mitochondria and the activation of a caspase cascade. Furthermore, at the molecular level, inhibition of CDK2 activity influences proapoptotic JNK signaling by reducing the protein level of c-Jun and suppressing the gentamicin-induced upregulation of c-Jun target genes Jun and Bim. Our in vivo studies reveal that Cdk2 gene knockout animals are significantly less sensitive to gentamicin ototoxicity compared to wild-type littermates. Altogether, our work ascertains the non-cell cycle role of CDK2 in regulating aminoglycoside-induced hair cell apoptosis and sheds lights on new potential strategies for hearing protection against ototoxicity.
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spelling pubmed-96067102022-10-28 CDK2 regulates aminoglycoside-induced hair cell death through modulating c-Jun activity: Inhibiting CDK2 to preserve hearing Tao, Litao Segil, Neil Front Mol Neurosci Neuroscience Sensory hair cell death caused by the ototoxic side effects of many clinically used drugs leads to permanent sensorineural hearing loss in patients. Aminoglycoside antibiotics are widely used and well-known for their ototoxicity, but the molecular mechanisms of aminoglycoside-induced hair cell death are not well understood. This creates challenges in our attempts to alleviate or prevent such adverse side effects. Here, we report a regulatory role of CDK2 in aminoglycoside-induced hair cell death. Utilizing organotypic cultures of cochleae from neonatal mice, we show that blocking CDK2 activity by either pharmaceutical inhibition or by Cdk2 gene knockout protects hair cells against the ototoxicity of gentamicin—one of the most commonly used aminoglycoside antibiotics—by interfering with intrinsic programmed cell death processes. Specifically, we show that CDK2 inhibition delays the collapse of mitochondria and the activation of a caspase cascade. Furthermore, at the molecular level, inhibition of CDK2 activity influences proapoptotic JNK signaling by reducing the protein level of c-Jun and suppressing the gentamicin-induced upregulation of c-Jun target genes Jun and Bim. Our in vivo studies reveal that Cdk2 gene knockout animals are significantly less sensitive to gentamicin ototoxicity compared to wild-type littermates. Altogether, our work ascertains the non-cell cycle role of CDK2 in regulating aminoglycoside-induced hair cell apoptosis and sheds lights on new potential strategies for hearing protection against ototoxicity. Frontiers Media S.A. 2022-10-13 /pmc/articles/PMC9606710/ /pubmed/36311033 http://dx.doi.org/10.3389/fnmol.2022.1013383 Text en Copyright © 2022 Tao and Segil. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Tao, Litao
Segil, Neil
CDK2 regulates aminoglycoside-induced hair cell death through modulating c-Jun activity: Inhibiting CDK2 to preserve hearing
title CDK2 regulates aminoglycoside-induced hair cell death through modulating c-Jun activity: Inhibiting CDK2 to preserve hearing
title_full CDK2 regulates aminoglycoside-induced hair cell death through modulating c-Jun activity: Inhibiting CDK2 to preserve hearing
title_fullStr CDK2 regulates aminoglycoside-induced hair cell death through modulating c-Jun activity: Inhibiting CDK2 to preserve hearing
title_full_unstemmed CDK2 regulates aminoglycoside-induced hair cell death through modulating c-Jun activity: Inhibiting CDK2 to preserve hearing
title_short CDK2 regulates aminoglycoside-induced hair cell death through modulating c-Jun activity: Inhibiting CDK2 to preserve hearing
title_sort cdk2 regulates aminoglycoside-induced hair cell death through modulating c-jun activity: inhibiting cdk2 to preserve hearing
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9606710/
https://www.ncbi.nlm.nih.gov/pubmed/36311033
http://dx.doi.org/10.3389/fnmol.2022.1013383
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