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Attenuation of Glucocorticoid Signaling through Targeted Degradation of p300 via the 26S Proteasome Pathway

Department of Medicine (Q.L., Y.A.L., R.J.G.H.) and Department of Biochemistry, Microbiology and Immunology (Y.A.L., R.J.G.H.), University of Ottawa, and the Ottawa Health Research Institute (Q.L., A.S., J.C., Y.A.L., R.J.G.H.), Ottawa, Ontario, Canada K1Y 4E9

Address all correspondence and requests for reprints to: Robert J. G. Haché or Qiao Li, The Ottawa Health Research Institute, 725 Parkdale Avenue, Ottawa, Ontario, Canada, K1Y 4E9. E-mail: rhache@ohri.ca or qli{at}ohri.ca.

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.

NURSA Molecule Pages Link:

Nuclear Receptors:   GR

Coregulators:   p300  |  SRC-1

Ligands:   Dexamethasone

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