Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1.
We previously demonstrated that activation of the glucocorticoid receptor (GR) initiates an antiapoptotic signal in the immortalized human mammary epithelial cell line MCF10A that is dependent on the GR's transcriptional activity. In this study, we show that the survival role of GR activation extends to protecting human breast cancer cells undergoing apoptosis after growth factor deprivation. Serum and glucocorticoid-regulated kinase-1 (sgk), a gene previously identified as a direct transcriptional target of the activated GR in a rat mammary tumor cell line, was rapidly induced after GR activation in human mammary epithelial cells. Furthermore, in the absence of all growth factors, ectopic sgk expression inhibited apoptosis, suggesting that SGK is a survival kinase. Finally, kinase-dead SGK expression inhibited the protection from apoptosis usually seen after GR activation. These findings suggest that SGK is an important downstream target of GR-mediated survival signaling and that it is distinct from other survival kinases because it can be primarily regulated at the level of transcription.
Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637, USA.
C A
CA
Mikosz
D R
DR
Brickley
M S
MS
Sharkey
T W
TW
Moran
S D
SD
Conzen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001940:Breast; D001943:Breast Neoplasms; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction; D004847:Epithelial Cells; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005938:Glucocorticoids / Q000494:pharmacology*; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D017874:Immediate-Early Proteins; D015735:Mifepristone / Q000494:pharmacology; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D014158:Transcription, Genetic; D000099184:Serum-Glucocorticoid Regulated Kinases
D003907:Dexamethasone; D005938:Glucocorticoids; D006133:Growth Substances; D017874:Immediate-Early Proteins; D015735:Mifepristone; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D011965:Receptors, Glucocorticoid; D000099184:Serum-Glucocorticoid Regulated Kinases