title: Huntingtin with an expanded polyglutamine repeat affects the Jab1-p27(Kip1) pathway.
abstract: Expansion of polyglutamine repeats is the cause of at least nine inherited human neurodegenerative disorders, including Huntington's disease (HD). It is widely accepted that deregulation of the transcriptional coactivator CBP by expanded huntingtin (htt) plays an important role in HD molecular pathogenesis. In this study, we report on a novel target of expanded polyglutamine stretches, the transcriptional coactivator Jun activation domain-binding protein 1 (Jab1), which shares DNA-sequence-specific transcription factor targets with CBP. Jab1 also plays a major role in the degradation of the cyclin-dependent-kinase inhibitor and putative transcription cofactor p27(Kip1). We found that Jab1 accumulates in aggregates when co-expressed with either expanded polyglutamine stretches or N-terminal fragments of mutant htt. In addition, the coactivator function of Jab1 was suppressed both by aggregated expanded polyglutamine solely and by mutant htt. Inhibition by mutant htt even preceded the appearance of microscopic aggregation. In an exon 1 HD cell model, we found that endogenous Jab1 could be recruited into aggregates and that this was accompanied by the accumulation of p27(Kip1). Accumulation of p27(Kip1) was also found in brains derived from HD patients. The repression of Jab1 by various mechanisms coupled with an increase of p27(Kip1) at late stages may have important transcriptional effects. In addition, the interference with the Jab1-p27(Kip1) pathway may contribute to the observed lower incidence of cancer in HD patients and may also be relevant for the understanding of the molecular pathogenesis of polyglutamine disorders in general.
authors.affiliation: Department of Neurology, Shengjing Hospital of China Medical University, Sanhao Street 36, Shenyang 110003, China. congshuyan@hotmail.com
authors.forename: S Y
authors.initials: SY
authors.lastname: Cong
authors.forename: B A
authors.initials: BA
authors.lastname: Pepers
authors.forename: T T
authors.initials: TT
authors.lastname: Zhou
authors.forename: H
authors.initials: H
authors.lastname: Kerkdijk
authors.forename: R A
authors.initials: RA
authors.lastname: Roos
authors.forename: G J
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: J C
authors.initials: JC
authors.lastname: Dorsman
mesh_terms: D015153:Blotting, Western; D000075686:COP9 Signalosome Complex; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000187:drug effects*; D042622:DNA Repeat Expansion; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects*; D008156:Luciferases / Q000378:metabolism; D009154:Mutation / Q000235:genetics / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000494:pharmacology*; D016716:PC12 Cells; D010447:Peptide Hydrolases / Q000187:drug effects*; D010455:Peptides / Q000235:genetics* / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C436291:CDKN1B protein, human; C086055:HTT protein, human; D000071058:Huntingtin Protein; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D050760:Cyclin-Dependent Kinase Inhibitor p27; C097188:polyglutamine; D008156:Luciferases; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex