Functions of Fos phosphorylation in bone homeostasis, cytokine response and tumorigenesis
Mice lacking c-fos develop osteopetrosis due to a block in osteoclast differentiation. Carboxy-terminal phosphorylation of Fos on serine 374 by ERK1/2 and serine 362 by RSK1/2 regulates Fos stability and transactivation potential in vitro . To assess the physiological relevance of Fos phosphorylatio...
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Published in | Oncogene Vol. 30; no. 13 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
29.11.2010
|
Online Access | Get full text |
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Summary: | Mice lacking
c-fos
develop osteopetrosis due to a block in osteoclast differentiation. Carboxy-terminal phosphorylation of Fos on serine 374 by ERK1/2 and serine 362 by RSK1/2 regulates Fos stability and transactivation potential
in vitro
. To assess the physiological relevance of Fos phosphorylation
in vivo
, serine 362 and/or serine 374 were replaced by alanine (Fos362A, Fos374A and FosAA) or by phospho-mimetic aspartic acid (FosDD). Homozygous mutants were healthy and skeletogenesis was largely unaffected. Fos C-terminal phosphorylation, predominantly on serine 374, was found important for osteoclast differentiation
in vitro
and affected lipopolysaccharide (LPS)-induced cytokine response
in vitro
and
in vivo
. Importantly, skin papilloma development was delayed in FosAA, Fos362A and
Rsk2
-deficient mice, accelerated in FosDD mice and unaffected in Fos374A mutants. Furthermore, the related Fos protein and putative RSK2 target Fra1 failed to substitute for Fos in papilloma development. This indicates that phosphorylation of serines 362 and 374 exerts context-dependent roles in modulating Fos activity
in vivo
. Inhibition of Fos C-terminal phosphorylation on serine 362 by targeting RSK2 might be of therapeutic relevance for skin tumors. |
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Bibliography: | Present address: Division of Genetics, Beth Israel Deaconess Medical Center, Boston, MA, USA Present address: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria |
ISSN: | 0950-9232 1476-5594 |
DOI: | 10.1038/onc.2010.542 |