Aberrant E2F activation by polyglutamine expansion of androgen receptor in SBMA neurotoxicity.
Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder caused by a polyglutamine repeat (polyQ) expansion within the human androgen receptor (AR). Unlike other neurodegenerative diseases caused by abnormal polyQ expansion, the onset of SBMA depends on androgen binding to mutant human polyQ-AR proteins. This is also observed in Drosophila eyes ectopically expressing the polyQ-AR mutants. We have genetically screened mediators of androgen-induced neurodegeneration caused by polyQ-AR mutants in Drosophila eyes. We identified Rbf (Retinoblastoma-family protein), the Drosophila homologue of human Rb (Retinoblastoma protein), as a neuroprotective factor. Androgen-dependent association of Rbf or Rb with AR was remarkably potentiated by aberrant polyQ expansion. Such potentiated Rb association appeared to attenuate recruitment of histone deacetyltransferase 1 (HDAC1), a corepressor of E2F function. Either overexpression of Rbf or E2F deficiency in fly eyes reduced the neurotoxicity of the polyQ-AR mutants. Induction of E2F function by polyQ-AR-bound androgen was suppressed by Rb in human neuroblastoma cells. We conclude that abnormal expansion of polyQ may potentiate innate androgen-dependent association of AR with Rb. This appears to lead to androgen-dependent onset of SBMA through aberrant E2F transactivation caused by suppressed histone deacetylation.
Suzuki
Eriko
E
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Zhao
Yue
Y
Ito
Saya
S
Sawatsubashi
Shun
S
Murata
Takuya
T
Furutani
Takashi
T
Shirode
Yuko
Y
Yamagata
Kaoru
K
Tanabe
Masahiko
M
Kimura
Shuhei
S
Ueda
Takashi
T
Fujiyama
Sally
S
Lim
Jinseon
J
Matsukawa
Hiroyuki
H
Kouzmenko
Alexander P
AP
Aigaki
Toshiro
T
Tabata
Tetsuya
T
Takeyama
Ken-ichi
K
Kato
Shigeaki
S
D000728:Androgens / Q000494:pharmacology; D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009134:Muscular Atrophy, Spinal / Q000378:metabolism* / Q000473:pathology*; D050505:Mutant Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D011944:Receptors, Androgen / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
D000728:Androgens; D029721:Drosophila Proteins; D050684:E2F Transcription Factors; C496298:E2f1 protein, Drosophila; D008024:Ligands; D050505:Mutant Proteins; D010455:Peptides; C099965:Rbf protein, Drosophila; D011944:Receptors, Androgen; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C097188:polyglutamine