title: Sgk1 activates MDM2-dependent p53 degradation and affects cell proliferation, survival, and differentiation.
abstract: 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.
authors.affiliation: Department of Experimental and clinical Medicine G. Salvatore, Faculty of Medicine, University Magna Graecia at Catanzaro, Catanzaro, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Amato
authors.forename: Lucia
authors.initials: L
authors.lastname: D'Antona
authors.forename: Giovanni
authors.initials: G
authors.lastname: Porciatti
authors.forename: Valter
authors.initials: V
authors.lastname: Agosti
authors.forename: Miranda
authors.initials: M
authors.lastname: Menniti
authors.forename: Cinzia
authors.initials: C
authors.lastname: Rinaldo
authors.forename: Nicola
authors.initials: N
authors.lastname: Costa
authors.forename: Emanuele
authors.initials: E
authors.lastname: Bellacchio
authors.forename: Stefano
authors.initials: S
authors.lastname: Mattarocci
authors.forename: Giorgio
authors.initials: G
authors.lastname: Fuiano
authors.forename: Silvia
authors.initials: S
authors.lastname: Soddu
authors.forename: Marco G
authors.initials: MG
authors.lastname: Paggi
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Nicola
authors.initials: N
authors.lastname: Perrotti
mesh_terms: 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
chemical_list: 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