Relative resistance of SGK1 knockout mice against chemical carcinogenesis.
The serum and glucocorticoid inducible kinase SGK1 was originally cloned from mammary tumor cells. SGK1 was found to be up-regulated in a variety of tumors, but down-regulated in several distinct tumors. Thus, evidence for a role of SGK1 in tumor growth remained conflicting. According to in vitro observations, SGK1 is up-regulated by the oncogene beta-catenin and negatively regulates the proapoptotic transcription factor FOXO3a, which in turn stimulates transcription of the Bcl2-interacting mediator BIM. This study aimed to define the role of SGK1 in colon carcinoma in vivo. SGK1 knockout mice (sgk1(-/-)) and their wild type littermates (sgk1(+/+)) were subjected to chemical cancerogenesis (intraperitoneal injection of 20 mg/kg 1,2-dimethylhydrazine followed by three cycles of 30 g/L synthetic dextran sulfate sodium for 7 days). Moreover, SGK1 was silenced in HEK293 cells. FOXO3a and BIM protein abundance was determined by Western blotting and immunohistochemistry. Following chemical cancerogenesis, sgk1(-/-)mice developed significantly less colonic tumors than sgk1(+/+)mice. According to Western blotting and immunohistochemistry, SGK1 deficiency enhanced the expression of FOXO3a and BIM both, in vitro and in vivo. SGK1 deficiency counteracts the development of colonic tumors, an effect at least in part due to up-regulation of FOXO3a and BIM.
Nasir
Omaima
O
Department of Physiology, University of Tuebingen, Germany.
Wang
Kan
K
Föller
Michael
M
Gu
Shuchen
S
Bhandaru
Madhuri
M
Ackermann
Teresa F
TF
Boini
Krishna M
KM
Mack
Andreas
A
Klingel
Karin
K
Amato
Rosario
R
Perrotti
Nicola
N
Kuhl
Dietmar
D
Behrens
Jürgen
J
Stournaras
Christos
C
Lang
Florian
F
D019813:1,2-Dimethylhydrazine; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D000072224:Bcl-2-Like Protein 11; D015687:Cell Hypoxia; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D005786:Gene Expression Regulation; D006801:Humans; D017874:Immediate-Early Proteins / Q000172:deficiency* / Q000502:physiology*; D007668:Kidney / Q000196:embryology; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D000099184:Serum-Glucocorticoid Regulated Kinases
D019813:1,2-Dimethylhydrazine; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases; C000606775:BCL2L11 protein, human; C000606776:Bcl2l11 protein, mouse; C499517:FOXO3 protein, human