title: Deficiency of the transcriptional regulator p8 results in increased autophagy and apoptosis, and causes impaired heart function.
abstract: 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.
authors.affiliation: Molecular Cardiology Research Institute, Tufts Medical Center and Department of Medicine, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Derek K
authors.initials: DK
authors.lastname: Kong
authors.forename: Serban P
authors.initials: SP
authors.lastname: Georgescu
authors.forename: Carla
authors.initials: C
authors.lastname: Cano
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Aronovitz
authors.forename: Juan Lucio
authors.initials: JL
authors.lastname: Iovanna
authors.forename: Richard D
authors.initials: RD
authors.lastname: Patten
authors.forename: John M
authors.initials: JM
authors.lastname: Kyriakis
authors.forename: Sandro
authors.initials: S
authors.lastname: Goruppi
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism / Q000235:genetics; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics; D017353:Gene Deletion; D020868:Gene Silencing; D006321:Heart / Q000503:physiopathology*; D006334:Heart Function Tests; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D055550:Protein Stability; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D044767:Ubiquitin-Protein Ligases
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D044767:Ubiquitin-Protein Ligases; C090121:BNIP3 protein, human; C499517:FOXO3 protein, human; C491643:NUPR1 protein, human; C491644:Nupr1 protein, mouse; C109741:Nupr1 protein, rat; C404219:Rnf19 protein, mouse