Sgk1 activates MDM2-dependent p53 degradation and affects cell proliferation, survival, and differentiation.
Serum and glucocorticoid regulated kinase 1 (Sgk1) is a serine-threonine kinase that is activated by serum, steroids, insulin, vasopressin, and interleukin 2 at the transcriptional and post-translational levels. Sgk1 is also important in transduction of growth factors and steroid-dependent survival signals and may have a role in the development of resistance to cancer chemotherapy. In the present paper, we demonstrate that Sgk1 activates MDM2-dependent p53 ubiquitylation. The results were obtained in RKO cells and other cell lines by Sgk1-specific RNA silencing and were corroborated in an original mouse model as well as in transiently and in stably transfected HeLa cells expressing wild-type or dominant negative Sgk1 mutant. Sgk1 contributes to cell survival, cell-cycle progression, and epithelial de-differentiation. We also show that the effects of Sgk1 on the clonogenic potential of different cancer cells depend on the expression of wild-type p53. Since transcription of Sgk1 is activated by p53, we propose a finely tuned feedback model where Sgk1 down-regulates the expression of p53 by enhancing its mono- and polyubiquitylation.
Amato
Rosario
R
Department of Experimental and clinical Medicine G. Salvatore, Faculty of Medicine, University Magna Graecia at Catanzaro, Catanzaro, Italy.
D'Antona
Lucia
L
Porciatti
Giovanni
G
Agosti
Valter
V
Menniti
Miranda
M
Rinaldo
Cinzia
C
Costa
Nicola
N
Bellacchio
Emanuele
E
Mattarocci
Stefano
S
Fuiano
Giorgio
G
Soddu
Silvia
S
Paggi
Marco G
MG
Lang
Florian
F
Perrotti
Nicola
N
D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53; D000099184:Serum-Glucocorticoid Regulated Kinases; C497206:MDM2 protein, human