title: c-Jun regulates the stability of anti-apoptotic ΔNp63 in amyloid-β-induced apoptosis.
abstract: p63, the structural and functional homologue of p53, is expressed either as a full-length isoform, containing a transactivation (TA) domain (TAp63), or as a truncated isoform, which lacks TA (ΔNp63). Amyloid-β (Aβ) incubation of neuronal cells results in stress-induced cell death through poorly understood mechanisms. We investigated the role of p63 in Aβ-induced stress. Our results show that Aβ-induced apoptosis of rat PC12 neuronal-like cells and primary cortical neurons was associated with stabilization of pro-apoptotic TAp63 and, most importantly, degradation of anti-apoptotic ΔNp63 through a MAPK- and proteasome-dependent mechanism. This was associated with increased c-Jun, and partially modulated by tauroursodeoxycholic acid. As expected, classic genotoxic insults resulted in c-Jun upregulation and concomitant ΔNp63 reduction. Endogenous and ectopic ΔNp63 expression was also markedly reduced by c-Jun overexpression. Further, Aβ-mediated ΔNp63 degradation occurred in a c-Jun-dependent manner. Downregulation of c-Jun expression by specific c-Jun siRNA abrogated the reduction of ΔNp63 levels following Aβ insult, whereas overexpression of c-Jun led to its degradation. c-Jun significantly decreased ΔNp63 half-life. Together, these findings demonstrate that the abundance of anti-apoptotic ΔNp63 in response to Aβ-induced cell stress is regulated by a c-Jun-dependent mechanism, and highlight the importance of finding novel targets for potential therapeutic intervention.
authors: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
authors: Maria B
authors: MB
authors: Fonseca
authors: Ana F
authors: AF
authors: Nunes
authors: Cecília M P
authors: CM
authors: Rodrigues
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006207:Half-Life; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D016716:PC12 Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D014162:Transfection / Q000379:methods; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D020929:Mitogen-Activated Protein Kinase Kinases; D046988:Proteasome Endopeptidase Complex