Huntingtin with an expanded polyglutamine repeat affects the Jab1-p27(Kip1) pathway
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...
| Hlavní autoři: | , , , , , , |
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| Médium: | Článek |
| Jazyk: | English |
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Elsevier
2012-06-01
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| Edice: | Neurobiology of Disease |
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| On-line přístup: | http://www.sciencedirect.com/science/article/pii/S0969996112000794 |
| _version_ | 1831800628280557568 |
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| author | S.Y. Cong B.A. Pepers T.T. Zhou H. Kerkdijk R.A. Roos G.J. van Ommen J.C. Dorsman |
| author_facet | S.Y. Cong B.A. Pepers T.T. Zhou H. Kerkdijk R.A. Roos G.J. van Ommen J.C. Dorsman |
| author_sort | S.Y. Cong |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T18:06:43Z |
| format | Article |
| id | doaj.art-ff78b4e6e7f14a6fb8b89a271d4bc21c |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-22T18:06:43Z |
| publishDate | 2012-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-ff78b4e6e7f14a6fb8b89a271d4bc21c2022-12-21T18:17:44ZengElsevierNeurobiology of Disease1095-953X2012-06-01463673681Huntingtin with an expanded polyglutamine repeat affects the Jab1-p27(Kip1) pathwayS.Y. Cong0B.A. Pepers1T.T. Zhou2H. Kerkdijk3R.A. Roos4G.J. van Ommen5J.C. Dorsman6Department of Neurology, Shengjing Hospital of China Medical University, Sanhao Street 36, Shenyang 110003, China; Center for Human and Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; Correspondence to: S.-Y. Cong, Department of Neurology, Shengjing Hospital of China Medical University, Sanhao Street 36, Shenyang 110003, China. Fax: +86 24 23198285.Center for Human and Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The NetherlandsLaboratory of Chromatin Biology, Department of Medical Cell Biology of Ministry of Education and Public Health of China, China Medical University, Beier Road 92, Shenyang 110001, ChinaCenter for Human and Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The NetherlandsDepartment of Neurology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The NetherlandsCenter for Human and Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The NetherlandsCenter for Human and Clinical Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands; Correspondence to: J. Dorsman, Department of Clinical Genetics, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. Fax: +31 20 4448285.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.http://www.sciencedirect.com/science/article/pii/S0969996112000794HuntingtinPolyglutamineJab1p27(Kip1)Transcriptional deregulation |
| spellingShingle | S.Y. Cong B.A. Pepers T.T. Zhou H. Kerkdijk R.A. Roos G.J. van Ommen J.C. Dorsman Huntingtin with an expanded polyglutamine repeat affects the Jab1-p27(Kip1) pathway Neurobiology of Disease Huntingtin Polyglutamine Jab1 p27(Kip1) Transcriptional deregulation |
| title | Huntingtin with an expanded polyglutamine repeat affects the Jab1-p27(Kip1) pathway |
| title_full | Huntingtin with an expanded polyglutamine repeat affects the Jab1-p27(Kip1) pathway |
| title_fullStr | Huntingtin with an expanded polyglutamine repeat affects the Jab1-p27(Kip1) pathway |
| title_full_unstemmed | Huntingtin with an expanded polyglutamine repeat affects the Jab1-p27(Kip1) pathway |
| title_short | Huntingtin with an expanded polyglutamine repeat affects the Jab1-p27(Kip1) pathway |
| title_sort | huntingtin with an expanded polyglutamine repeat affects the jab1 p27 kip1 pathway |
| topic | Huntingtin Polyglutamine Jab1 p27(Kip1) Transcriptional deregulation |
| url | http://www.sciencedirect.com/science/article/pii/S0969996112000794 |
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