Regulation of expanded polyglutamine protein aggregation and nuclear localization by the glucocorticoid receptor

Marc I. Diamond, Melissa R. Robinson, Keith R. Yamamoto

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Spinobulbar muscular atrophy and Huntington's disease are caused by polyglutamine expansion in the androgen receptor and huntingtin, respectively, and their pathogenesis has been associated with abnormal nuclear localization and aggregation of truncated forms of these proteins. Here we show, in diverse cell types, that glucocorticoids can up- or down- modulate aggregation and nuclear localization of expanded polyglutamine polypeptides derived from the androgen receptor and huntingtin through specific regulation of gene expression. Wild-type glucocorticoid receptor (GR), as well as C-terminal deletion derivatives, suppressed the aggregation and nuclear localization of these polypeptides, whereas mutations within the DNA binding domain and N terminus of GR abolished this activity. Surprisingly, deletion of a transcriptional regulatory domain within the GR N terminus markedly increased aggregation and nuclear localization of the expanded polyglutamine proteins. Thus, aggregation and nuclear localization of expanded polyglutamine proteins are regulated cellular processes that can be modulated by a well-characterized transcriptional regulator, the GR. Our findings suggest approaches to study the molecular pathogenesis and selective neuronal degeneration of polyglutamine expansion diseases.

Original languageEnglish (US)
Pages (from-to)657-661
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number2
DOIs
StatePublished - Jan 18 2000

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Glucocorticoid Receptors
Nuclear Proteins
Androgen Receptors
Atrophic Muscular Disorders
Peptides
Proteins
Huntington Disease
Gene Expression Regulation
Muscular Diseases
Glucocorticoids
polyglutamine
Mutation
DNA

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Regulation of expanded polyglutamine protein aggregation and nuclear localization by the glucocorticoid receptor. / Diamond, Marc I.; Robinson, Melissa R.; Yamamoto, Keith R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 2, 18.01.2000, p. 657-661.

Research output: Contribution to journalArticle

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