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Identification of Target Genes Involved in the Antiproliferative Effect of Glucocorticoids Reveals a Role for Nuclear Factor-B Repression

Departments 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, SE-141 57 Huddinge, Sweden

Address all correspondence and requests for reprints to: Professor Sam Okret, Department of Medical Nutrition, Karolinska Institutet, Karolinska University Hospital Huddinge, Novum, SE-141 86 Huddinge, Sweden. E-mail: Sam.Okret{at}mednut.ki.se.

Glucocorticoid hormones (GCs) exert an antiproliferative effect on most cells. However, the molecular mechanism is still largely unclear. We investigated the antiproliferative mechanism by GCs in human embryonic kidney 293 cells with stably introduced glucocorticoid receptor (GR) mutants that discriminate between cross-talk with nuclear factor-B (NF-B) and activator protein-1 signaling, transactivation and transrepression, and antiproliferative vs. non-antiproliferative responses. Using the GR mutants, we here demonstrate a correlation between repression of NF-B signaling and antiproliferative response. Gene expression profiling of endogenous genes in cells containing mutant GRs identified a limited number of genes that correlated with the antiproliferative response. This included a GC-mediated up-regulation of the NF-B-inhibitory protein IB, in line with repression of NF-B signaling being important in the GC-mediated antiproliferative response. Interestingly, the GC-stimulated expression of IB was a direct effect despite the inability of the GR mutant to transactivate through a GC-responsive element. Selective expression of IB in human embryonic kidney 293 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-B is an important mechanism in the antiproliferative response to GCs.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ  |  GR

Ligands:   Dexamethasone

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