Modulation of glucocorticoid receptor transcriptional activation, phosphorylation, and growth inhibition by p27Kip1

The cyclin- dependent kinase inhibitor p27(Kip1) is frequently inactivated in human cancers. Glucocorticoids, acting through the glucocorticoid receptor ( GR), are frequently used to treat certain malignancies and are growth inhibitive, but the relationship between GR activity and p27 status has not been explored. We have therefore examined GR- dependent transcriptional activation, receptor phosphorylation, and glucocorticoid-dependent growth inhibition in p27- deficient ( p27(-/-)) murine embryonic fibroblasts ( MEFs). We find that GR transcriptional enhancement as well as receptor phosphorylation at two putative cyclin- dependent kinase sites are elevated in p27(-/-) MEFs, relative to control cells. This increased GR transcriptional activation appears to be mediated through the GR N terminus, and coexpression of the GR N- terminal coactivator, DRIP150, further enhanced GR- dependent transcriptional activation. Furthermore, p27(-/-) MEFs are partially resistant to the growth inhibitory effects of glucocorticoids. Thus, p27 appears to be an important element in the GR transcription and growth inhibitory responses.