Cell cycle regulation of glucocorticoid receptor function.
Glucocorticoid receptor (GR) nuclear translocation, transactivation and phosphorylation were examined during the cell cycle in mouse L cell fibroblasts. Glucocorticoid-dependent transactivation of the mouse mammary tumor virus promoter was observed in G0 and S phase synchronized L cells, but not in G2 synchronized cells. G2 effects were selective on the glucocorticoid hormone signal transduction pathway, since glucocorticoid but not heavy metal induction of the endogenous Metallothionein-1 gene was also impaired in G2 synchronized cells. GRs that translocate to the nucleus of G2 synchronized cells in response to dexamethasone treatment were not efficiently retained there and redistributed to the cytoplasmic compartment. In contrast, GRs bound by the glucocorticoid antagonist RU486 were efficiently retained within nuclei of G2 synchronized cells. Inefficient nuclear retention was observed for both dexamethasone- and RU486-bound GRs in L cells that actively progress through G2 following release from an S phase arrest. Finally, site-specific alterations in GR phosphorylation were observed in G2 synchronized cells suggesting that cell cycle regulation of specific protein kinases and phosphatases could influence nuclear retention, recycling and transactivation activity of the GR.
Hsu
S C
SC
Department of Biological Sciences, University of Pittsburgh, PA 15260.
Qi
M
M
DeFranco
D B
DB
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002453:Cell Cycle / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D007739:L Cells; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology; D010766:Phosphorylation; D011965:Receptors, Glucocorticoid / Q000302:isolation & purification / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation
D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone