Modulation of glucocorticoid receptor transcriptional activation, phosphorylation, and growth inhibition by p27Kip1.
The cyclin-dependent kinase inhibitor p27Kip1 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.
Wang
Zhen
Z
Department of Microbiology, New York University Cancer Institute, New York University School of Medicine, New York, New York 10016, USA.
Garabedian
Michael J
MJ
D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002455:Cell Division; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003907:Dexamethasone / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000502:physiology; D010766:Phosphorylation; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D015534:Trans-Activators; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
C117286:CRSP protein, human; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011965:Receptors, Glucocorticoid; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003907:Dexamethasone; D042846:CDC2-CDC28 Kinases; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2