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Stem cell factor promotes mast cell survival via inactivation of FOXO3a mediated transcriptional induction and MEK regulated phosphorylation of the pro-apoptotic protein Bim
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
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Article in journal (Refereed) Submitted
URN: urn:nbn:se:uu:diva-92472OAI: oai:DiVA.org:uu-92472DiVA: diva2:165560
Available from: 2004-11-26 Created: 2004-11-26Bibliographically approved
In thesis
1. Regulation of Mast Cell Survival
Open this publication in new window or tab >>Regulation of Mast Cell Survival
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mast cells are long-lived effector cells of importance for both acute and chronic inflammations. Mast cells can be activated in many different ways, leading to the release of inflammatory mediators. In contrast to most other inflammatory cells, activated mast cells have the capacity to recover, regranulate and thereby be activated again.

In this thesis I have investigated the mechanisms involved in regulating activation-induced mast cell survival. We have found that cross-linking of FcεRI-bound IgE with an antigen (IgER-CL) induces a survival program in mast cells. Upon IgER-CL, mouse and human mast cells upregulate the pro-survival Bcl-2 family gene A1/Bfl-1. A1-/- mast cells degranulate upon FcεRI activation but they cannot recover most likely due to the lack of A1. Sensitized and provoked A1-/- mice exhibit lower amounts of mast cells compared to littermate controls. In contrast to mast cells, no Bfl-1 expression or survival promotion can be detected in basophils after IgER-CL. Another mast cell secretagogue, an adenosine receptor agonist, neither promoted upregulation of A1 nor survival.

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. We have found that SCF promotes survival through Akt-mediated inhibition of the forkhead transcription factor FOXO3a and its transcriptional target Bim, a BH3-only pro-apoptotic protein. SCF-treatment prevents upregulation of Bim protein expression and leads to an upregulation of Bim phosphorylation through PI3-kinase and MEK-dependent pathways. Overexpression of FOXO3a causes an upregulation of Bim and induces mast cell apoptosis, even in the presence of SCF.

Taken together, the work in this thesis demonstrates that A1/Bfl-1 and Bim play key roles in mast cell survival. These findings might be of importance in understanding the mechanisms of mast cell longevity and hence for possible new therapeutics used for mast cell-associated inflammations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 66 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1396
Pathology, mast cell, A1, Bfl-1, Bim, Bcl-2 family members, basophil, SCF, forkhead, survival, Patologi
National Category
Cell and Molecular Biology
urn:nbn:se:uu:diva-4703 (URN)91-554-6118-2 (ISBN)
Public defence
2004-12-17, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:15
Available from: 2004-11-26 Created: 2004-11-26Bibliographically approved

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