title: Signal transducer and activator of transcription 3 (STAT3) degradation by proteasome controls a developmental switch in neurotrophin dependence.
abstract: Neonatal brains develop through a program that eliminates about half of the neurons. During this period, neurons depend on neurotrophins for their survival. Recently, we reported that, at the conclusion of the naturally occurring death period, neurons become neurotrophin-independent and, further, that this developmental switch is achieved by the emergence of a second survival pathway mediated by signal transducer and activator of transcription 3 (STAT3). Here I show that calcineurin plays a key role in controlling the developmental switch in mouse hippocampal neurons. Calcineurin promotes the degradation of STAT3 via the ubiquitin-proteasome pathway. Inhibition of calcineurin acutely increases total levels of STAT3 as well as its activated forms, resulting in decreased levels of the tumor suppressor p53 and its proapoptotic target, Bax. In vivo and in vitro, calcineurin regulates levels of STAT3 and neurotrophin dependence. TMF/ARA 160 (TATA element modulatory factor/androgen receptor co-activator 160), the key mediator of STAT3 ubiquitination, is required for calcineurin-dependent STAT3 degradation. Thus, these results show that the ubiquitin-proteasome pathway controls the critical developmental switch of neurotrophin dependence in the newborn hippocampus.
authors.affiliation: Laboratory of Molecular Biology, NINDS, National Institutes of Health, Bethesda, Maryland 20892, USA. sachikom@ninds.nih.gov
authors.forename: Sachiko
authors.initials: S
authors.lastname: Murase
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D019703:Calcineurin / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005260:Female; D000077614:Golgi Matrix Proteins; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016559:Tacrolimus / Q000494:pharmacology; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494827:Bax protein, mouse; D004268:DNA-Binding Proteins; D000077614:Golgi Matrix Proteins; D009414:Nerve Growth Factors; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C554202:Tmf1 protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D033921:Vesicular Transport Proteins; D051028:bcl-2-Associated X Protein; D044767:Ubiquitin-Protein Ligases; D019703:Calcineurin; D046988:Proteasome Endopeptidase Complex; D016559:Tacrolimus
keywords: Bax; Calcineurin; Developmental Death; Neurotrophins; STAT3; Ubiquitin-Proteasome Pathway; p53