Attenuation of glucocorticoid signaling through targeted degradation of p300 via the 26S proteasome pathway

被引:41
作者
Li, Q
Su, A
Chen, JH
Lefebvre, YA
Haché, RJG
机构
[1] Ottawa Hlth Res Inst, Ottawa, ON K1Y 4E9, Canada
[2] Univ Ottawa, Dept Med, Ottawa, ON K1Y 4E9, Canada
[3] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON K1Y 4E9, Canada
关键词
D O I
10.1210/me.2002-0154
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The effects of acetylation on gene expression are complex, with changes in chromatin accessibility intermingled with direct effects on transcriptional regulators. For the nuclear receptors, both positive and negative effects of acetylation on specific gene transcription have been observed. We report that p300 and steroid receptor coactivator 1 interact transiently with the glucocorticoid receptor and that the acetyltransferase activity of p300 makes an important contribution to glucocorticoid receptor-mediated transcription. Treatment of cells with the deacetylase inhibitor, sodium butyrate, inhibited steroid-induced transcription and altered the transient association of glucocorticoid receptor with p300 and steroid receptor coactivator 1. Additionally, sustained sodium butyrate treatment induced the degradation of p300 through the 26S proteasome pathway. Treatment. with the proteasome inhibitor MG132 restored both the level of p300 protein and the transcriptional response to, steroid over 20 h of treatment. These results reveal new levels for the regulatory control of gene expression by acetylation and suggest feedback control on p300 activity.
引用
收藏
页码:2819 / 2827
页数:9
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