1. Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death.
- Author
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Okazawa H, Rich T, Chang A, Lin X, Waragai M, Kajikawa M, Enokido Y, Komuro A, Kato S, Shibata M, Hatanaka H, Mouradian MM, Sudol M, and Kanazawa I
- Subjects
- Aged, Animals, Ataxin-1, Ataxins, Carrier Proteins metabolism, Cell Nucleus genetics, Cell Nucleus metabolism, Cell Nucleus pathology, Cell Survival genetics, Cells, Cultured, Cerebellum pathology, Cerebellum physiopathology, DNA-Binding Proteins, Disease Models, Animal, Female, Humans, Inclusion Bodies genetics, Inclusion Bodies metabolism, Inclusion Bodies pathology, Macromolecular Substances, Mice, Nerve Tissue Proteins metabolism, Neurons pathology, Nuclear Proteins metabolism, Peptides genetics, Protein Structure, Tertiary genetics, RNA Polymerase II genetics, RNA Polymerase II metabolism, Spinocerebellar Ataxias metabolism, Spinocerebellar Ataxias pathology, Trinucleotide Repeat Expansion genetics, Carrier Proteins genetics, Cell Death genetics, Cerebellum metabolism, Genes, Regulator genetics, Nerve Tissue Proteins genetics, Neurons metabolism, Nuclear Proteins genetics, Spinocerebellar Ataxias genetics
- Abstract
PQBP-1 was isolated on the basis of its interaction with polyglutamine tracts. In this study, using in vitro and in vivo assays, we show that the association between ataxin-1 and PQBP-1 is positively influenced by expanded polyglutamine sequences. In cell lines, interaction between the two molecules induces apoptotic cell death. As a possible mechanism underlying this phenomenon, we found that mutant ataxin-1 enhances binding of PQBP-1 to the C-terminal domain of RNA polymerase II large subunit (Pol II). This reduces the level of phosphorylated Pol II and transcription. Our results suggest the involvement of PQBP-1 in the pathology of spinocerebellar ataxia type 1 (SCA1) and support the idea that modified transcription underlies polyglutamine-mediated pathology.
- Published
- 2002
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