SGK1-dependent intestinal tumor growth in APC-deficient mice.
Adenomatous polyposis coli (APC) is inactivated in familial adenomatous polyposis and sporadic colorectal cancer. Mice carrying defective APC (apc(Min/+)) spontaneously develop gastrointestinal tumors. APC binds GSK3beta, which phosphorylates beta-catenin thus fostering its degradation. beta-catenin upregulates the serum- and glucocorticoid-inducible kinase Sgk1, which inhibits GSK3beta. The present study explored the role of SGK1 in tumor growth of apc(Min/+)mice. apc(Min/+)mice were crossed with SGK1-knockout mice (sgk1(-/-)) and their wild type littermates (sgk1(+/+)) generating apc(Min/+)/sgk1(-/-)mice and apc(Min/+)/sgk1(+/+)mice. beta-catenin abundance was determined by Western blotting and confocal microscopy. As a result apc(Min/+)/sgk1(+/+)mice developed significantly more intestinal tumors than apc(Min/+)/sgk1(-/-)mice. Following chemical cancerogenesis, colonic beta-catenin protein abundance was significantly higher in sgk1(+/+)mice than in sgk1(-/-)mice. beta-catenin expression was significantly increased in HEK293 cells treated with dexamethasone for upregulation of Sgk1. In conclusion, SGK1 expression favors the development of intestinal tumors in APC-deficient mice, an effect at least partially due to enhanced beta-catenin protein abundance.
Wang
Kan
K
Department of Physiology, University of Tuebingen, 72076 Tuebingen, Germany.
Gu
Shuchen
S
Nasir
Omaima
O
Föller
Michael
M
Ackermann
Teresa F
TF
Klingel
Karin
K
Kandolf
Reinhard
R
Kuhl
Dietmar
D
Stournaras
Christos
C
Lang
Florian
F
D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D017874:Immediate-Early Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
D025601:Adenomatous Polyposis Coli Protein; D018931:Antineoplastic Agents, Hormonal; D003907:Dexamethasone; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D051176:beta Catenin; D000099184:Serum-Glucocorticoid Regulated Kinases; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse