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Repression of p65 Transcriptional Activation by the Glucocorticoid Receptor in the Absence of Receptor-Coactivator Interactions

Department of Biochemistry and Molecular Biology, Pharmacia Corp., St. Louis, Missouri 63198

Address all correspondence and requests for reprints to: Deepak S. Lala, Molecular Sciences and Technologies, Ann Arbor Laboratories, Pfizer Inc., 2800 Plymouth Road, Ann Arbor, Michigan 48105. E-mail: deepak.s.lala{at}pfizer.com.

Glucocorticoids are among the most potent antiinflammatory agents, acting through the glucocorticoid receptor (GR) to suppress gene expression of a variety of cytokines. This appears to be via transcriptional interference (or transrepression) of key regulatory factors such as nuclear factor-B and activator protein 1. Ligand-bound GR can also activate gene transcription (transactivation) via direct binding to glucocorticoid response elements. Transactivation by GR is potentiated by accessory coactivators such as steroid receptor coactivator 1 and peroxisome proliferator-activated receptor coactivator 1, whereas the role of these proteins in transrepression is unclear.

Here, we show that GR can recruit several coactivator receptor interacting domains in a ligand-dependent manner. All interactions require the charge clamp defined by K579/E755, while a subset also requires a second charge clamp defined by R585/D590, within the GR ligand-binding domain. A point mutation, E755A, abolished all GR-receptor interacting domain interactions and led to a decrease in GR-mediated transactivation, but did not significantly affect GR-mediated transrepression of Gal4-p65 activity. Overexpression of a GR-interacting coactivator peptide blocked transactivation but did not affect transrepression of p65 or TNF-induced IL-6 promoter activity. Finally, the GR antagonist RU486 did not recruit coactivators to GR but maintained the ability to transrepress p65 activity.

Our data suggest that different coactivators utilize distinct contact points to interact with GR. Although GR interactions with specific coactivators are critical for transactivation, they appear to be dispensable for at least certain aspects of GR-mediated transrepression of nuclear factor-B. This is consistent with the notion that all GR- mediated repression is not intrinsically linked to activation and can be separated mechanistically.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Coregulators:   RIP140  |  TRAP220  |  PGC-1  |  TIF1α  |  CBP  |  p300  |  SRC-1  |  GRIP1  |  AIB1  |  ARA70  |  CIA

Ligands:   Dexamethasone  |  RU486

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