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ZnT2 is a critical mediator of lysosomal-mediated cell death during early mammary gland involution

Mammary gland involution is the most dramatic example of physiological cell death. It occurs through an initial phase of lysosomal-mediated cell death (LCD) followed by mitochondrial-mediated apoptosis. Zinc (Zn) activates both LCD and apoptosis in vitro. The Zn transporter ZnT2 imports Zn into vesi...

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Autores principales: Hennigar, Stephen R., Seo, Young Ah, Sharma, Supriya, Soybel, David I., Kelleher, Shannon L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306139/
https://www.ncbi.nlm.nih.gov/pubmed/25620235
http://dx.doi.org/10.1038/srep08033
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author Hennigar, Stephen R.
Seo, Young Ah
Sharma, Supriya
Soybel, David I.
Kelleher, Shannon L.
author_facet Hennigar, Stephen R.
Seo, Young Ah
Sharma, Supriya
Soybel, David I.
Kelleher, Shannon L.
author_sort Hennigar, Stephen R.
collection PubMed
description Mammary gland involution is the most dramatic example of physiological cell death. It occurs through an initial phase of lysosomal-mediated cell death (LCD) followed by mitochondrial-mediated apoptosis. Zinc (Zn) activates both LCD and apoptosis in vitro. The Zn transporter ZnT2 imports Zn into vesicles and mitochondria and ZnT2-overexpression activates cell death in mammary epithelial cells (MECs). We tested the hypothesis that ZnT2-mediated Zn transport is critical for mammary gland involution in mice. Following weaning, ZnT2 abundance increased in lysosomes and mitochondria, which paralleled Zn accumulation in each of these organelles. Adenoviral expression of ZnT2 in lactating mouse mammary glands in vivo increased Zn in lysosomes and mitochondria and activated LCD and apoptosis, promoting a profound reduction in MECs and alveoli. Injection of TNFα, a potent activator of early involution, into the mammary gland fat pads of lactating mice increased ZnT2 and Zn in lysosomes and activated premature involution. Exposure of cultured MECs to TNFα redistributed ZnT2 to lysosomes and increased lysosomal Zn, which activated lysosomal swelling, cathepsin B release, and LCD. Our data implicate ZnT2 as a critical mediator of cell death during involution and importantly, that as an initial involution signal, TNFα redistributes ZnT2 to lysosomes to activate LCD.
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spelling pubmed-43061392015-02-05 ZnT2 is a critical mediator of lysosomal-mediated cell death during early mammary gland involution Hennigar, Stephen R. Seo, Young Ah Sharma, Supriya Soybel, David I. Kelleher, Shannon L. Sci Rep Article Mammary gland involution is the most dramatic example of physiological cell death. It occurs through an initial phase of lysosomal-mediated cell death (LCD) followed by mitochondrial-mediated apoptosis. Zinc (Zn) activates both LCD and apoptosis in vitro. The Zn transporter ZnT2 imports Zn into vesicles and mitochondria and ZnT2-overexpression activates cell death in mammary epithelial cells (MECs). We tested the hypothesis that ZnT2-mediated Zn transport is critical for mammary gland involution in mice. Following weaning, ZnT2 abundance increased in lysosomes and mitochondria, which paralleled Zn accumulation in each of these organelles. Adenoviral expression of ZnT2 in lactating mouse mammary glands in vivo increased Zn in lysosomes and mitochondria and activated LCD and apoptosis, promoting a profound reduction in MECs and alveoli. Injection of TNFα, a potent activator of early involution, into the mammary gland fat pads of lactating mice increased ZnT2 and Zn in lysosomes and activated premature involution. Exposure of cultured MECs to TNFα redistributed ZnT2 to lysosomes and increased lysosomal Zn, which activated lysosomal swelling, cathepsin B release, and LCD. Our data implicate ZnT2 as a critical mediator of cell death during involution and importantly, that as an initial involution signal, TNFα redistributes ZnT2 to lysosomes to activate LCD. Nature Publishing Group 2015-01-26 /pmc/articles/PMC4306139/ /pubmed/25620235 http://dx.doi.org/10.1038/srep08033 Text en Copyright © 2015, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Article
Hennigar, Stephen R.
Seo, Young Ah
Sharma, Supriya
Soybel, David I.
Kelleher, Shannon L.
ZnT2 is a critical mediator of lysosomal-mediated cell death during early mammary gland involution
title ZnT2 is a critical mediator of lysosomal-mediated cell death during early mammary gland involution
title_full ZnT2 is a critical mediator of lysosomal-mediated cell death during early mammary gland involution
title_fullStr ZnT2 is a critical mediator of lysosomal-mediated cell death during early mammary gland involution
title_full_unstemmed ZnT2 is a critical mediator of lysosomal-mediated cell death during early mammary gland involution
title_short ZnT2 is a critical mediator of lysosomal-mediated cell death during early mammary gland involution
title_sort znt2 is a critical mediator of lysosomal-mediated cell death during early mammary gland involution
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306139/
https://www.ncbi.nlm.nih.gov/pubmed/25620235
http://dx.doi.org/10.1038/srep08033
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