Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim.
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.
Möller
Christine
C
Department of Genetics and Pathology, The Rudbeck Laboratory, Uppsala University, Sweden.
Alfredsson
Jessica
J
Engström
Maria
M
Wootz
Hanna
H
Xiang
Zou
Z
Lennartsson
Johan
J
Jönsson
Jan-Ingvar
JI
Nilsson
Gunnar
G
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000378:metabolism*; D002470:Cell Survival; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008407:Mast Cells / Q000166:cytology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019089:Stem Cell Factor / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002352:Carrier Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019089:Stem Cell Factor; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases