Allele-specific regulation of mutant Huntingtin by Wig1, a downstream target of p53

Sun Hong Kim, Neelam Shahani, Byoung Ii Bae, Juan Sbodio, Youjin Chung, Kazuhiro Nakaso, Bindu D. Paul, Akira Sawa

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2514-2524
Number of pages11
JournalHuman Molecular Genetics
Volume25
Issue number12
StatePublished - Jun 15 2016

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p53 Genes
Huntington Disease
Alleles
Pathology
Cerebral Cortex
Cell Biology
Molecular Biology
Up-Regulation
Animal Models
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Kim, S. H., Shahani, N., Bae, B. I., Sbodio, J., Chung, Y., Nakaso, K., ... Sawa, A. (2016). Allele-specific regulation of mutant Huntingtin by Wig1, a downstream target of p53. Human Molecular Genetics, 25(12), 2514-2524.

Allele-specific regulation of mutant Huntingtin by Wig1, a downstream target of p53. / Kim, Sun Hong; Shahani, Neelam; Bae, Byoung Ii; Sbodio, Juan; Chung, Youjin; Nakaso, Kazuhiro; Paul, Bindu D.; Sawa, Akira.

In: Human Molecular Genetics, Vol. 25, No. 12, 15.06.2016, p. 2514-2524.

Research output: Contribution to journalArticle

Kim, SH, Shahani, N, Bae, BI, Sbodio, J, Chung, Y, Nakaso, K, Paul, BD & Sawa, A 2016, 'Allele-specific regulation of mutant Huntingtin by Wig1, a downstream target of p53', Human Molecular Genetics, vol. 25, no. 12, pp. 2514-2524.
Kim SH, Shahani N, Bae BI, Sbodio J, Chung Y, Nakaso K et al. Allele-specific regulation of mutant Huntingtin by Wig1, a downstream target of p53. Human Molecular Genetics. 2016 Jun 15;25(12):2514-2524.
Kim, Sun Hong ; Shahani, Neelam ; Bae, Byoung Ii ; Sbodio, Juan ; Chung, Youjin ; Nakaso, Kazuhiro ; Paul, Bindu D. ; Sawa, Akira. / Allele-specific regulation of mutant Huntingtin by Wig1, a downstream target of p53. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 12. pp. 2514-2524.
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