Nuclear integration of glucocorticoid receptor and nuclear factor-kappaB signaling by CREB-binding protein and steroid receptor coactivator-1.
The p65 (RelA) component of nuclear factor-kappaB (NF-kappaB) and the glucocorticoid receptor (GR) mutually repress each other's ability to activate transcription. Both of these transcriptional activators depend upon the coactivators CREB-binding protein (CBP) and steroid receptor coactivator-1 (SRC-1) for maximal activity. Here we show that increased levels of CBP relieves the inhibition of glucocorticoid-mediated repression of NF-kappaB activity and the NF-kappaB-mediated repression of GR activity. SRC-1 can relieve the NF-kappaB-mediated repression of GR activity. We propose that cross-talk between the p65 component of NF-kappaB and glucocorticoid receptors is due, at least in part, to nuclear competition for limiting amounts of the coactivators CBP and SRC-1, thus providing a novel mechanism for decreasing expression of genes involved in the inflammatory response.
Sheppard
K A
KA
Vascular Research Division, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
Phelps
K M
KM
Williams
A J
AJ
Thanos
D
D
Glass
C K
CK
Rosenfeld
M G
MG
Gerritsen
M E
ME
Collins
T
T
D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D050882:CREB-Binding Protein; D002417:Cattle; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D051548:Histone Acetyltransferases; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D056920:Nuclear Receptor Coactivator 1; D009838:Oligodeoxyribonucleotides; D011485:Protein Binding; D020239:Receptor Cross-Talk; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D016328:NF-kappa B; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D011965:Receptors, Glucocorticoid; D015534:Trans-Activators; D014157:Transcription Factors; D050882:CREB-Binding Protein; D051548:Histone Acetyltransferases; D056920:Nuclear Receptor Coactivator 1