Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription.
At least eight inherited neurodegenerative diseases are caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches are implicated, the molecular mechanisms of neurodegeneration remain unclear. We found that expanded polyQ stretches preferentially bind to TAFII130, a coactivator involved in cAMP-responsive element binding protein (CREB)-dependent transcriptional activation, and strongly suppress CREB-dependent transcriptional activation. The suppression of CREB-dependent transcription and the cell death induced by polyQ stretches were restored by the co-expression of TAFII130. Our results indicate that interference of transcription by the binding of TAFII130 with expanded polyQ stretches is involved in the pathogenetic mechanisms underlying neurodegeneration.
Shimohata
T
T
Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
Nakajima
T
T
Yamada
M
M
Uchida
C
C
Onodera
O
O
Naruse
S
S
Kimura
T
T
Koide
R
R
Nozaki
K
K
Sano
Y
Y
Ishiguro
H
H
Sakoe
K
K
Ooshima
T
T
Sato
A
A
Ikeuchi
T
T
Oyake
M
M
Sato
T
T
Aoyagi
Y
Y
Hozumi
I
I
Nagatsu
T
T
Takiyama
Y
Y
Nishizawa
M
M
Goto
J
J
Kanazawa
I
I
Davidson
I
I
Tanese
N
N
Takahashi
H
H
Tsuji
S
S
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001284:Atrophy / Q000235:genetics / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D016923:Cell Death; D002460:Cell Line; D002466:Cell Nucleolus / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D017362:Cyclic AMP Response Element-Binding Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D005917:Globus Pallidus / Q000378:metabolism / Q000473:pathology; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D019680:Trinucleotide Repeat Expansion; D020798:Two-Hybrid System Techniques; D001616:beta-Galactosidase / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D008164:Luminescent Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins; C101882:TAF4 protein, human; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D001616:beta-Galactosidase