Recruitment of cAMP-response element-binding protein and histone deacetylase has opposite effects on glucocorticoid receptor gene transcription.

Glucocorticoids control the synthesis of the glucocorticoid receptor (GR) in various tissues through a negative feedback regulation of the mRNA. In this study, we have identified feedback regulatory domains in the human GR gene promoter and examined the roles of GR, the cAMP-response element-binding protein (CREB), and HDAC-6 in association ...
with promoter elements of the human GR gene. Using breast cancer T47D and HeLa-GR cells, we identify specific negative glucocorticoid-response elements in the GR gene. The feedback regulatory domains were also involved in interactions with CREB. GR-bound negative glucocorticoid-response elements recruited HDAC-6, and this was dependent on treatment with dexamethasone. Both CREB and HDAC-6 formed complexes with GR-dexamethasone. The HDAC-6 LXXLL motif between amino acids 313 and 418 made direct contact with the GR AF-1 domain. Interestingly enough, although the level of GR decreased in CREB knockdown cells, it was elevated in HDAC-6 knockdown cells. Our results suggest that CREB-P is dephosphorylated and that HDAC-6 is recruited by the GR, and they play opposite roles in the negative feedback regulation of the GR gene.
Mesh Terms:
Binding Sites, Cell Line, Tumor, Chromatin Immunoprecipitation, Cyclic AMP Response Element-Binding Protein, Dexamethasone, Hela Cells, Histone Deacetylases, Humans, Immunoprecipitation, Kinetics, Phosphorylation, Protein Binding, RNA, Small Interfering, Receptors, Glucocorticoid, Sequence Deletion
J. Biol. Chem.
Date: Feb. 12, 2010
Download Curated Data For This Publication
122518
Switch View:
  • Interactions 6