The glucocorticoid receptor represses cyclin D1 by targeting the Tcf-beta-catenin complex.
The ability of glucocorticoids (GCs) to regulate cell proliferation plays an important role in their therapeutic use. The canonical Wnt pathway, which promotes the proliferation of many cancers and differentiated tissues, is an emerging target for the actions of GCs, albeit existing links between these signaling pathways are indirect. By screening known Wnt target genes for their ability to respond differently to GCs in cells whose proliferation is either positively or negatively regulated by GCs, we identified c-myc, c-jun, and cyclin D1, which encode rate-limiting factors for G(1) progression of the cell cycle. Here we show that in U2OS/GR cells, which are growth-arrested by GCs, the glucocorticoid receptor (GR) represses cyclin D1 via Tcf-beta-catenin, the transcriptional effector of the canonical Wnt pathway. We demonstrate that GR can bind beta-catenin in vitro, suggesting that GC and Wnt signaling pathways are linked directly through their effectors. Down-regulation of beta-catenin by RNA interference impeded the expression of cyclin D1 but not of c-myc or c-jun and had no significant effect on the proliferation of U2OS/GR cells. Although these results revealed that beta-catenin and cyclin D1 are not essential for the regulation of U2OS/GR cell proliferation, considering the importance of the Wnt pathway for proliferation and differentiation of other cells, the repression of Tcf-beta-catenin activity by GR could open new possibilities for tissue-selective GC therapies.
Takayama
Sachiko
S
Institute of Molecular Biology and Department of Chemistry, University of Oregon, Eugene, OR 97403-1229, USA.
Rogatsky
Inez
I
Schwarcz
Leslie E
LE
Darimont
Beatrice D
BD
D000818:Animals; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology; D008156:Luciferases / Q000235:genetics; D008175:Lung Neoplasms; D012516:Osteosarcoma; D011401:Promoter Regions, Genetic / Q000502:physiology; D034741:RNA, Small Interfering; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051820:TCF Transcription Factors / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D008156:Luciferases