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Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim

Moller, C; Alfredsson, J; Kraft, Maria LU ; Wootz, H; Xiang, Z; Lennartsson, J; Jönsson, Jan-Ingvar LU and Nilsson, G (2005) In Blood 106(4). p.1330-1336
Abstract
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... (More)
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 (MEKJMAPK) 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
106
issue
4
pages
1330 - 1336
publisher
American Society of Hematology
external identifiers
  • wos:000231167700036
  • pmid:15855272
  • scopus:23744515285
ISSN
1528-0020
DOI
10.1182/blood-2004-12-4792
language
English
LU publication?
yes
id
4f8560c4-cc94-40bf-bd70-ff955d71219a (old id 229392)
date added to LUP
2007-10-05 09:46:01
date last changed
2017-10-08 03:38:48
@article{4f8560c4-cc94-40bf-bd70-ff955d71219a,
  abstract     = {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 (MEKJMAPK) 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.},
  author       = {Moller, C and Alfredsson, J and Kraft, Maria and Wootz, H and Xiang, Z and Lennartsson, J and Jönsson, Jan-Ingvar and Nilsson, G},
  issn         = {1528-0020},
  language     = {eng},
  number       = {4},
  pages        = {1330--1336},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim},
  url          = {http://dx.doi.org/10.1182/blood-2004-12-4792},
  volume       = {106},
  year         = {2005},
}