RRC ID 60793
Author Hoshino M, Qi ML, Yoshimura N, Miyashita T, Tagawa K, Wada Y, Enokido Y, Marubuchi S, Harjes P, Arai N, Oyanagi K, Blandino G, Sudol M, Rich T, Kanazawa I, Wanker EE, Saitoe M, Okazawa H.
Title Transcriptional repression induces a slowly progressive atypical neuronal death associated with changes of YAP isoforms and p73.
Journal J. Cell Biol.
Abstract Transcriptional disturbance is implicated in the pathology of polyglutamine diseases, including Huntington's disease (HD). However, it is unknown whether transcriptional repression leads to neuronal death or what forms that death might take. We found transcriptional repression-induced atypical death (TRIAD) of neurons to be distinct from apoptosis, necrosis, or autophagy. The progression of TRIAD was extremely slow in comparison with other types of cell death. Gene expression profiling revealed the reduction of full-length yes-associated protein (YAP), a p73 cofactor to promote apoptosis, as specific to TRIAD. Furthermore, novel neuron-specific YAP isoforms (YAPDeltaCs) were sustained during TRIAD to suppress neuronal death in a dominant-negative fashion. YAPDeltaCs and activated p73 were colocalized in the striatal neurons of HD patients and mutant huntingtin (htt) transgenic mice. YAPDeltaCs also markedly attenuated Htt-induced neuronal death in primary neuron and Drosophila melanogaster models. Collectively, transcriptional repression induces a novel prototype of neuronal death associated with the changes of YAP isoforms and p73, which might be relevant to the HD pathology.
Volume 172(4)
Pages 589-604
Published 2006-2-13
DOI 10.1083/jcb.200509132
PII jcb.200509132
PMID 16461361
PMC PMC2063678
MeSH Adaptor Proteins, Signal Transducing / genetics* Amanitins / pharmacology Amino Acid Sequence Animals Apoptosis Regulatory Proteins / genetics* Apoptosis Regulatory Proteins / metabolism* Cell Death / genetics Cell Survival / drug effects Cells, Cultured DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Disease Models, Animal Down-Regulation / drug effects Down-Regulation / physiology Drosophila melanogaster / genetics Embryo Research Genes, Tumor Suppressor Humans Huntington Disease / metabolism* Huntington Disease / pathology Mice Molecular Sequence Data Mutagenesis, Insertional Neurons / metabolism Neurons / pathology* Nuclear Proteins / genetics Nuclear Proteins / metabolism* Phosphoproteins / genetics* Protein Isoforms / genetics Protein Isoforms / metabolism RNA, Small Interfering / pharmacology Rats Time Factors Trans-Activators / drug effects Trans-Activators / physiology Transcription Factors Transcription, Genetic / drug effects* Tumor Protein p73 Tumor Suppressor Proteins
Times Cited 59