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PNAS 97 (2): 657-661
Copyright © 2000 by the National Academy of Sciences.
Vol. 97, Issue 2, 657-661, January 18, 2000
Cell Biology
Regulation of expanded polyglutamine protein aggregation and
nuclear localization by the glucocorticoid receptor
Marc I.
Diamond*, ,
Melissa R.
Robinson , and
Keith R.
Yamamoto,§
Departments of * Neurology and Cellular and Molecular
Pharmacology, and School of Medicine, University of
California, San Francisco, CA 94143
Contributed by Keith R. Yamamoto, November 23, 1999
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.
§
To whom reprint requests should be addressed at: Box
0450, University of California, San Francisco, CA 94143-0450. E-mail: yamamoto{at}cgl.ucsf.edu.
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