Interaction between mutant ataxin-1 and PQBP-1 affects transcription and cell death.
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.
Okazawa
Hitoshi
H
Department of Neurology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan. okazawa@tmin.ac.jp
Rich
Tina
T
Chang
Alex
A
Lin
Xi
X
Waragai
Masaaki
M
Kajikawa
Masunori
M
Enokido
Yasushi
Y
Komuro
Akihiko
A
Kato
Seishi
S
Shibata
Masao
M
Hatanaka
Hiroshi
H
Mouradian
M Maral
MM
Sudol
Marius
M
Kanazawa
Ichiro
I
D000368:Aged; D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000235:genetics*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D005260:Female; D005809:Genes, Regulator / Q000235:genetics*; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D046911:Macromolecular Substances; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C119246:PQBP1 protein, human; D010455:Peptides; C492272:Pqbp1 protein, mouse; C097188:polyglutamine; D012319:RNA Polymerase II