Distinct domains of the RelA NF-kappaB subunit are required for negative cross-talk and direct interaction with the glucocorticoid receptor.
The RelA subunit of NF-kappaB and the glucocorticoid receptor mutually repress each others transcriptional activity, thus providing a mechanism for immunosuppression. Deletion analysis of the glucocorticoid receptor has shown that the DNA binding domain and the ligand binding domain are essential components for repression. Here, we show by deletions and point mutations that both the Rel homology domain and the transactivation domains of RelA are required for repression of the transcriptional activity of the glucocorticoid receptor in intact cells. However, only the Rel homology domain of RelA was found to associate with the glucocorticoid receptor in vitro. RelA mutants, not able to repress glucocorticoid receptor activity, but still able to dimerize, behaved as transdominant inhibitors of the repressive activity of wild type RelA. Furthermore, we show that the 13 S E1A protein is able to interfere with the transrepressive activity of RelA. We propose that negative cross-talk between the glucocorticoid receptor and RelA is due to direct interaction via the Rel homology domain of RelA and the DNA binding domain of the glucocorticoid receptor in combination with interference by the transactivation domains of RelA with the transcriptional activity of the glucocorticoid receptor.
Wissink
S
S
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht, The Netherlands.
van Heerde
E C
EC
Schmitz
M L
ML
Kalkhoven
E
E
van der Burg
B
B
Baeuerle
P A
PA
van der Saag
P T
PT
D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D004247:DNA / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011487:Protein Conformation; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D051996:Transcription Factor RelA; D015533:Transcriptional Activation
D017500:Adenovirus E1A Proteins; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D051996:Transcription Factor RelA; D004247:DNA