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Functions of Fos phosphorylation in bone homeostasis, cytokine response and tumourigenesis

Oncogene volume 30, pages 1506–1517 (2011)Cite this article

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Abstract

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 was 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 tumours.

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Acknowledgements

We are very grateful to Drs K Matsuo, Y Takada and R Khokha for critical comments and helpful suggestions, Drs F Mulero and RP Marshall for help with micro-computed tomography, U Moehle-Steinlein, E Andres, HC Theussl and V Komnenovic for technical assistance. The project was initiated at the IMP, which is funded by Boehringer Ingelheim (BI). EFW is funded by the BBVA-Foundation and by an ERC advanced Grant. Part of this work was funded by an EMBO postdoctoral fellowship to LB and the NoE Cells into Organs (LSHM-CT-2003-504468) program of the European Community.

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Author notes

  1. R Zenz

    Present address: 5Current address: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.,

  2. M O Reschke: Currrent address: Division of Genetics, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Authors and Affiliations

  1. Genes, Development and Disease Group, F-BBVA Cancer Cell Biology programme, National Cancer Research Centre (CNIO), Madrid, Spain

    L Bakiri, M O Reschke, H A Gefroh, M H Idarraga, K Polzer, R Zenz, G Schett & E F Wagner

  2. Research Institute of Molecular Pathology (IMP), Vienna, Austria

    M H Idarraga

  3. Department of Internal Medicine 3, University of Erlangen-Nurenberg, Erlangen, Germany

    K Polzer & G Schett

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Correspondence to E F Wagner.

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Bakiri, L., Reschke, M., Gefroh, H. et al. Functions of Fos phosphorylation in bone homeostasis, cytokine response and tumourigenesis. Oncogene 30, 1506–1517 (2011). https://doi.org/10.1038/onc.2010.542

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