Selectivity of Cell Cycle Regulation of Glucocorticoid Receptor Function (*)

The restricted expression of some genes to distinct stages of the cell cycle is often brought about through alterations in the activity and/or abundance of specific transcription factors. Many cells have been shown to be unresponsive to glucocorticoid hormone action during the G2 phase of the mammalian cell cycle, suggesting that some activities of the glucocorticoid receptor (GR), a ligand-activated transcription factor, are subjected to cell cycle control. We show here that GR insensitivity in G2 is selective, affecting receptor-mediated transactivation from a simple glucocorticoid response element, but not repression from a composite glucocorticoid response element. Since glucocorticoid-dependent down-regulation of GR protein levels is also unaffected in G2, distinct activities of the receptor that participate in this homologous down-regulation must be operating as effectively in G2-synchronized cells as in asynchronous cells. Finally, the phosphorylation state of the GR is altered in G2-synchronized cells reflecting, in part, both site-specific phosphorylation and dephosphorylation events. These results suggest that, while GR may be a target for cell cycle regulated kinases and phosphatases, the resulting changes in receptor phosphorylation have an impact only on selected GR functions.