Conditional modulation of glucocorticoid receptor activities by CREB-binding protein (CBP) and p300

Coactivators of nuclear receptors are integral components of the signal tra nsduction pathways of steroid hormones. Here, we show that one of the major coactivators of the glucocorticoid receptor (GF:), CREB-binding protein (C BP), can also function conditionally as a negative regulator of its activit ies. Indeed, CBP suppressed the responsiveness of the mouse mammary tumor v irus (MMTV) promoter to dexamethasone in a dose-dependent fashion in HeLa a nd A204 cells. Similarly, this protein suppressed the responsiveness of sev eral glucocorticoid-responsive element (GRE)-containing synthetic promoters . Using deletion mutants of CBP, we localized the repressor effect of this protein to its N-terminal domain and showed that it was independent of the histone acetyltransferase and coactivator-binding domains but dependent upo n its GR-binding domain. We also demonstrated functional differentiation be tween CBP and other coactivators, including SRC-1 and the CBP-related prote in p300, both of which influenced GR signaling in a positive fashion. In fa ct, p300 completely antagonized the suppressive effects of CBP in a dose-de pendent fashion, probably by competing with this protein at the level of th e transcription complex. These findings suggest that CBP and p300 may funct ion additively or antagonistically to each other depending on their relativ e concentrations and type of target tissue, to influence the sensitivity of tissues to glucocorticoids. (C) 1999 Published by Elsevier Science Ltd. Al l rights reserved.