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 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2010 |
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| Erschienen: |
2010 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:21 |
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| Enthalten in: |
Molecular biology of the cell - 21(2010), 8 vom: 15. Apr., Seite 1335-49 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kong, Derek K [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 17.09.2010 Date Revised 15.08.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1091/mbc.E09-09-0818 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM195342402 |
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| 100 | 1 | |a Kong, Derek K |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Deficiency of the transcriptional regulator p8 results in increased autophagy and apoptosis, and causes impaired heart function |
| 264 | 1 | |c 2010 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 17.09.2010 | ||
| 500 | |a Date Revised 15.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a BNIP3 protein, human |2 NLM | |
| 650 | 7 | |a Basic Helix-Loop-Helix Transcription Factors |2 NLM | |
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| 700 | 1 | |a Georgescu, Serban P |e verfasserin |4 aut | |
| 700 | 1 | |a Cano, Carla |e verfasserin |4 aut | |
| 700 | 1 | |a Aronovitz, Mark J |e verfasserin |4 aut | |
| 700 | 1 | |a Iovanna, Juan Lucio |e verfasserin |4 aut | |
| 700 | 1 | |a Patten, Richard D |e verfasserin |4 aut | |
| 700 | 1 | |a Kyriakis, John M |e verfasserin |4 aut | |
| 700 | 1 | |a Goruppi, Sandro |e verfasserin |4 aut | |
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