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This version published online on November 4, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0294
A more recent version of this article appeared on March 1, 2005
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Submitted on July 22, 2004
Accepted on October 26, 2004

Identification of target genes involved in the anti-proliferative effect of glucocorticoids reveals a role for nuclear factor-{kappa}B repression

LARS-GÖRAN BLADH, JOHAN LIDÉN, AHMAD PAZIRANDEH, INGALILL RAFTER, KARIN DAHLMAN-WRIGHT, STEFAN NILSSON, and SAM OKRET*

Dept. of Medical Nutrition (L-G.B., A.P., I.R., S.O.) and Biosciences (J.L., K.D-W.), Karolinska Institutet, Karolinska University Hospital Huddinge, Novum, SE-141 86 Huddinge, Sweden and KaroBio AB (L-G.B., S.N.), Novum, Huddinge, Sweden

* To whom correspondence should be addressed. E-mail: Sam.Okret{at}mednut.ki.se.

Glucocorticoid hormones (GCs) exert an anti-proliferative effect on most cells. However, the molecular mechanism is still largely unclear. We investigated the anti-proliferative mechanism by GCs in HEK293 cells with stably introduced glucocorticoid receptor (GR) mutants that discriminate between cross-talk with nuclear factor-kappaB (NF-{kappa}B) and activator protein-1 (AP-1) signaling, transactivation and transrepression, and anti-proliferative vs. non-anti-proliferative responses. Using the GR mutants, we here demonstrate a correlation between repression of NF-{kappa}B signaling and anti-proliferative response. Gene expression profiling of endogenous genes in cells containing mutant GRs identified a limited number of genes that correlated with the anti-proliferative response. This included a GC-mediated up-regulation of the NF-{kappa}B inhibitory protein I{kappa}B{alpha}, in line with repression of NF-{kappa}B signaling being important in the GC-mediated anti-proliferative response. Interestingly, the GC-stimulated expression of I{kappa}B{alpha} was a direct effect despite the inability of the GR mutant to transactivate through a GC-responsive element. Selective expression of I{kappa}B{alpha} in HEK293 cells resulted in a decreased percentage of cells in the S/G2/M phase and impaired cell proliferation. These results demonstrate that GC-mediated inhibition of NF-{kappa}B is an important mechanism in the anti-proliferative response to GCs.
Key words: glucocorticoids • proliferation • gene expression profiling • NF-{kappa}B • AP-1

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ  |  GR
Ligands:   Dexamethasone



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