Allele-specific regulation of mutant Huntingtin by Wig1, a downstream target of p53.
Hum Mol Genet
; 25(12): 2514-2524, 2016 06 15.
Article
em En
| MEDLINE
| ID: mdl-27206983
ABSTRACT
p53 has been implicated in the pathophysiology of Huntington's disease (HD). Nonetheless, the molecular mechanism of how p53 may play a unique role in the pathology remains elusive. To address this question at the molecular and cellular biology levels, we initially screened differentially expressed molecules specifically dependent on p53 in a HD animal model. Among the candidate molecules, wild-type p53-induced gene 1 (Wig1) is markedly upregulated in the cerebral cortex of HD patients. Wig1 preferentially upregulates the level of mutant Huntingtin (Htt) compared with wild-type Htt. This allele-specific characteristic of Wig1 is likely to be explained by higher affinity binding to mutant Htt transcripts than normal counterpart for the stabilization. Knockdown of Wig1 level significantly ameliorates mutant Htt-elicited cytotoxicity and aggregate formation. Together, we propose that Wig1, a key p53 downstream molecule in HD condition, play an important role in stabilizing mutant Htt mRNA and thereby accelerating HD pathology in the mHtt-p53-Wig1 positive feedback manner.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Nucleares
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Proteínas de Transporte
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Proteína Supressora de Tumor p53
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Doença de Huntington
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Proteína Huntingtina
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Aged
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Aged80
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article