Yx. Tao et al., Mapping of glucocorticoid receptor DNA binding domain surfaces contributing to transrepression of NF-kappa B and induction of apoptosis, J BIOL CHEM, 276(4), 2001, pp. 2329-2332
Glucocorticoids (GCs) function, in part, through the ability of the glucoco
rticoid receptor (GR) to activate gene expression and in part through the t
ransrepression of AP-1 and NF-kappaB, Here we characterize the effect of GR
DNA binding domain (DBD) mutations, previously analyzed for changes in the
ability to activate gene expression or transrepress AP-1. We have identifi
ed a GR mutant capable of distinguishing between transrepression of NF-kapp
aB and AP-1. Using circular dichroism spectroscopy, we show that this mutat
ion does not appreciably alter GR DBD conformation, suggesting that functio
nal differences between the mutant and wild type protein are the result of
an alteration of a specific interaction surface. These data suggest that tr
ansrepression of NF-kappaB and AP-1 occurs through distinct protein-protein
interactions and argue against the hypothesis that transrepression occurs
through competition for a single coactivator protein. Introduction of these
mutations into GC-resistant CEM lymphoblastic T cells restored dexamethaso
ne (DEX)-mediated apoptosis as did wild type GR regardless of whether these
mutants were transrepression or activation defective. Thus, HEX-mediated a
poptosis in transformed T cells is more complex than originally appreciated
.