Essential role of RSK2 in c-Fos-dependent osteosarcoma development.
Inactivation of the growth factor-regulated S6 kinase RSK2 causes Coffin-Lowry syndrome in humans, an X-linked mental retardation condition associated with progressive skeletal abnormalities. Here we show that mice lacking RSK2 develop a progressive skeletal disease, osteopenia due to impaired osteoblast function and normal osteoclast differentiation. The phenotype is associated with decreased expression of Phex, an endopeptidase regulating bone mineralization. This defect is probably not mediated by RSK2-dependent phosphorylation of c-Fos on serine 362 in the C-terminus. However, in the absence of RSK2, c-Fos-dependent osteosarcoma formation is impaired. The lack of c-Fos phosphorylation leads to reduced c-Fos protein levels, which are thought to be responsible for decreased proliferation and increased apoptosis of transformed osteoblasts. Therefore, RSK2-dependent stabilization of c-Fos is essential for osteosarcoma formation in mice and may also be important for human osteosarcomas.
David
Jean-Pierre
JP
Research Institute of Molecular Pathology, Vienna, Austria.
Mehic
Denis
D
Bakiri
Latifa
L
Schilling
Arndt F
AF
Mandic
Vice
V
Priemel
Matthias
M
Idarraga
Maria Helena
MH
Reschke
Markus O
MO
Hoffmann
Oskar
O
Amling
Michael
M
Wagner
Erwin F
EF
D000818:Animals; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001842:Bone and Bones / Q000166:cytology / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D038921:Coffin-Lowry Syndrome / Q000235:genetics; D005260:Female; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D011859:Radiography; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*
D016760:Proto-Oncogene Proteins c-fos; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3
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