Cargando…

Deficiency of the Transcriptional Regulator p8 Results in Increased Autophagy and Apoptosis, and Causes Impaired Heart Function

Autophagy is a cytoprotective pathway used to degrade and recycle cytoplasmic content. Dysfunctional autophagy has been linked to both cancer and cardiomyopathies. Here, we show a role for the transcriptional regulator p8 in autophagy. p8 RNA interference (RNAi) increases basal autophagy markers in...

Descripción completa

Detalles Bibliográficos
Autores principales: Kong, Derek K., Georgescu, Serban P., Cano, Carla, Aronovitz, Mark J., Iovanna, Juan Lucio, Patten, Richard D., Kyriakis, John M., Goruppi, Sandro
Formato: Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854092/
https://www.ncbi.nlm.nih.gov/pubmed/20181828
http://dx.doi.org/10.1091/mbc.E09-09-0818
_version_ 1782180070469664768
author Kong, Derek K.
Georgescu, Serban P.
Cano, Carla
Aronovitz, Mark J.
Iovanna, Juan Lucio
Patten, Richard D.
Kyriakis, John M.
Goruppi, Sandro
author_facet Kong, Derek K.
Georgescu, Serban P.
Cano, Carla
Aronovitz, Mark J.
Iovanna, Juan Lucio
Patten, Richard D.
Kyriakis, John M.
Goruppi, Sandro
author_sort Kong, Derek K.
collection PubMed
description Autophagy is a cytoprotective pathway used to degrade and recycle cytoplasmic content. Dysfunctional autophagy has been linked to both cancer and cardiomyopathies. Here, we show a role for the transcriptional regulator p8 in autophagy. p8 RNA interference (RNAi) increases basal autophagy markers in primary cardiomyocytes, in H9C2 and U2OS cells, and decreases cellular viability after autophagy induction. This autophagy is associated with caspase activation and is blocked by atg5 silencing and by pharmacological inhibitors. FoxO3 transcription factor was reported to activate autophagy by enhancing the expression of autophagy-related genes. P8 expression represses FoxO3 transcriptional activity, and p8 knockdown affects FoxO3 nuclear localization. Thus, p8 RNAi increases FoxO3 association with bnip3 promoter, a known proautophagic FoxO3 target, resulting in higher bnip3 RNA and protein levels. Accordingly, bnip3 knockdown restores cell viability and blocks apoptosis of p8-deficient cells. In vivo, p8 −/− mice have higher autophagy and express higher cardiac bnip3 levels. These mice develop left ventricular wall thinning and chamber dilation, with consequent impaired cardiac function. Our studies provide evidence of a p8-dependent mechanism regulating autophagy by acting as FoxO3 corepressor, which may be relevant for diseases associated with dysregulated autophagy, as cardiovascular pathologies and cancer.
format Text
id pubmed-2854092
institution National Center for Biotechnology Information
language English
publishDate 2010
publisher The American Society for Cell Biology
record_format MEDLINE/PubMed
spelling pubmed-28540922010-06-30 Deficiency of the Transcriptional Regulator p8 Results in Increased Autophagy and Apoptosis, and Causes Impaired Heart Function Kong, Derek K. Georgescu, Serban P. Cano, Carla Aronovitz, Mark J. Iovanna, Juan Lucio Patten, Richard D. Kyriakis, John M. Goruppi, Sandro Mol Biol Cell Articles Autophagy is a cytoprotective pathway used to degrade and recycle cytoplasmic content. Dysfunctional autophagy has been linked to both cancer and cardiomyopathies. Here, we show a role for the transcriptional regulator p8 in autophagy. p8 RNA interference (RNAi) increases basal autophagy markers in primary cardiomyocytes, in H9C2 and U2OS cells, and decreases cellular viability after autophagy induction. This autophagy is associated with caspase activation and is blocked by atg5 silencing and by pharmacological inhibitors. FoxO3 transcription factor was reported to activate autophagy by enhancing the expression of autophagy-related genes. P8 expression represses FoxO3 transcriptional activity, and p8 knockdown affects FoxO3 nuclear localization. Thus, p8 RNAi increases FoxO3 association with bnip3 promoter, a known proautophagic FoxO3 target, resulting in higher bnip3 RNA and protein levels. Accordingly, bnip3 knockdown restores cell viability and blocks apoptosis of p8-deficient cells. In vivo, p8 −/− mice have higher autophagy and express higher cardiac bnip3 levels. These mice develop left ventricular wall thinning and chamber dilation, with consequent impaired cardiac function. Our studies provide evidence of a p8-dependent mechanism regulating autophagy by acting as FoxO3 corepressor, which may be relevant for diseases associated with dysregulated autophagy, as cardiovascular pathologies and cancer. The American Society for Cell Biology 2010-04-15 /pmc/articles/PMC2854092/ /pubmed/20181828 http://dx.doi.org/10.1091/mbc.E09-09-0818 Text en © 2010 by The American Society for Cell Biology
spellingShingle Articles
Kong, Derek K.
Georgescu, Serban P.
Cano, Carla
Aronovitz, Mark J.
Iovanna, Juan Lucio
Patten, Richard D.
Kyriakis, John M.
Goruppi, Sandro
Deficiency of the Transcriptional Regulator p8 Results in Increased Autophagy and Apoptosis, and Causes Impaired Heart Function
title Deficiency of the Transcriptional Regulator p8 Results in Increased Autophagy and Apoptosis, and Causes Impaired Heart Function
title_full Deficiency of the Transcriptional Regulator p8 Results in Increased Autophagy and Apoptosis, and Causes Impaired Heart Function
title_fullStr Deficiency of the Transcriptional Regulator p8 Results in Increased Autophagy and Apoptosis, and Causes Impaired Heart Function
title_full_unstemmed Deficiency of the Transcriptional Regulator p8 Results in Increased Autophagy and Apoptosis, and Causes Impaired Heart Function
title_short Deficiency of the Transcriptional Regulator p8 Results in Increased Autophagy and Apoptosis, and Causes Impaired Heart Function
title_sort deficiency of the transcriptional regulator p8 results in increased autophagy and apoptosis, and causes impaired heart function
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854092/
https://www.ncbi.nlm.nih.gov/pubmed/20181828
http://dx.doi.org/10.1091/mbc.E09-09-0818
work_keys_str_mv AT kongderekk deficiencyofthetranscriptionalregulatorp8resultsinincreasedautophagyandapoptosisandcausesimpairedheartfunction
AT georgescuserbanp deficiencyofthetranscriptionalregulatorp8resultsinincreasedautophagyandapoptosisandcausesimpairedheartfunction
AT canocarla deficiencyofthetranscriptionalregulatorp8resultsinincreasedautophagyandapoptosisandcausesimpairedheartfunction
AT aronovitzmarkj deficiencyofthetranscriptionalregulatorp8resultsinincreasedautophagyandapoptosisandcausesimpairedheartfunction
AT iovannajuanlucio deficiencyofthetranscriptionalregulatorp8resultsinincreasedautophagyandapoptosisandcausesimpairedheartfunction
AT pattenrichardd deficiencyofthetranscriptionalregulatorp8resultsinincreasedautophagyandapoptosisandcausesimpairedheartfunction
AT kyriakisjohnm deficiencyofthetranscriptionalregulatorp8resultsinincreasedautophagyandapoptosisandcausesimpairedheartfunction
AT goruppisandro deficiencyofthetranscriptionalregulatorp8resultsinincreasedautophagyandapoptosisandcausesimpairedheartfunction