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Blood, 15 August 2005, Vol. 106, No. 4, pp. 1330-1336.
Prepublished online as a Blood First Edition Paper on April 26, 2005; DOI 10.1182/blood-2004-12-4792.
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Submitted December 16, 2004
Accepted April 16, 2005
Stem cell factor promotes mast cell survival via inactivation of FOXO3a mediated transcriptional induction and MEK regulated phosphorylation of the pro-apoptotic protein Bim
Christine Moller, Jessica Alfredsson, Maria Engstrom, Hanna Wootz, Zou Xiang, Johan Lennartsson, Jan-Ingvar Jonsson, and Gunnar Nilsson*
Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
Division of Molecular Medicine, Department of Laboratory Medicine, University Hospital MAS, Lund University, Malmo, Sweden
Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden
Division of Molecular Medicine, Department of Laboratory Medicine, University Hospital MAS, Lund University, Malmo, Sweden; Division of Cell Biology, Department of Biomedicine and Surgery, Linkoping University, Linkoping, Sweden
Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; Department of Medicine, Karolinska Institutet, Stockholm, Sweden
* Corresponding author; email: Gunnar.Nilsson{at}medks.ki.se.
Mast cells are found in tissues throughout the body where they play important roles in the regulation of inflammatory responses. One characteristic feature of mast cells is their longevity. Although it is well established that mast cell survival is dependent on stem cell factor (SCF), it has not been described how this process is regulated. Herein, we report that SCF promotes mast cell survival through inactivation of the Forkhead transcription factor FOXO3a and down-regulation and phosphorylation of its target Bim, a BH3-only pro-apoptotic protein. SCF induced a rapid and transient phosphorylation of Akt and FOXO3a. SCF-treatment prevented up-regulation of Bim protein expression and led to increased Bim phosphorylation. Bim-phosphorylation was inhibited by PD98059 and LY294002 treatment, suggesting the involvement of MEK/MAPK and PI3-kinase pathways in this process. Overexpression of phosphorylation-deficient FOXO3a caused an up-regulation of Bim and induced mast cell apoptosis even in the presence of SCF. Mast cell apoptosis induced by the phosphorylation-deficient FOXO3a was attenuated in bim-/- mast cells. Since apoptosis is abnormally reduced in bim-/- mast cells, these data provide evidence that Akt-mediated inhibition of FOXO3a and its transcription target Bim provides an important mechanism by which SCF acts to prevent apoptosis in mast cells.
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