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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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IMMUNOBIOLOGY
Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim
Christine Möller,
Jessica Alfredsson,
Maria Engström,
Hanna Wootz,
Zou Xiang,
Johan Lennartsson,
Jan-Ingvar Jönsson, and
Gunnar Nilsson
From the Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; the Division of Molecular Medicine, Department of Laboratory Medicine, University Hospital MAS, Lund University, Malmö, Sweden; the Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden; the Division of Cell Biology, Department of Biomedicine and Surgery, Linköping University, Linköping, Sweden; and the Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
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 (forkhead box, class O3A) and down-regulation and phosphorylation of its target Bim (Bcl-2 [B-cell lymphoma-2] interacting modulator of cell death), a Bcl-2 homology 3 (BH3)–only proapoptotic protein. SCF induced a rapid and transient phosphorylation of Akt (protein kinase B) 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 mitogen-activated protein kinase kinase/mitogen-activated protein kinase (MEK/MAPK) and phosphatidylinositol 3 (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. Because 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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