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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-92672OAI: oai:DiVA.org:uu-92672DiVA: diva2:165836
Available from: 2005-03-11 Created: 2005-03-11Bibliographically approved
In thesis
1. Molecular Studies of Mast Cell Migration and Apoptosis: Two Ways of Regulating Mast Cell Numbers at Sites of Inflammation
Open this publication in new window or tab >>Molecular Studies of Mast Cell Migration and Apoptosis: Two Ways of Regulating Mast Cell Numbers at Sites of Inflammation
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Upon activation mast cells release numerous proinflammatory mediators. With this feature, mast cells play an important role in host defense against pathogens, and are involved in tissue remodeling and wound healing. However, in cases of excessive inflammation the effects of mast cells are detrimental. This is observed in allergy, asthma, rheumatoid arthritis, atherosclerosis, certain types of heart failure, and in several other chronic destructive inflammations. Mast cell numbers are typically increased at inflammatory sites. There they act both directly, as effector cells, and in a regulatory manner, secreting agents that recruit and activate other immune cells.

The studies presented here investigated mechanisms regulating mast cell numbers at sites of inflammation, focusing on cell migration and regulation of survival/apoptosis. We report that SCF-induced mast cell migration requires p38 MAP kinase activity. Moreover, we found that SCF-mediated mast cell survival is regulated through downregulation of the proapoptotic Bcl-2 family member Bim, as well as through phoshorylation of Bim. SCF seems to control Bim protein levels via FOXO transcription factors, and to induce phosphorylation of Bim via the Mek/Erk and the PI3-kinase/Akt signaling pathways. Furthermore, mast cell death triggered by deprivation of SCF and/or IL-3 involves the Bim protein, as demonstrated using bim-/- mast cells. Additional studies revealed that IgE-receptor activation, which occurs in allergy, promotes both prosurvival and proapoptotic signaling events. This includes upregulation of Bim and the prosurvival Bcl-XL and A1, as well as phosphorylation of Akt, FOXO factors, GSK-3β, IκB-α, Bad, and Bim. The simultaneous stimulation of prosurvival and proapoptotic signaling events could be a way to fine-tune the fate of mast cells after IgE-receptor activation and degranulation.

The new insights about mechanisms involved in mast cell migration and regulation of survival/apoptosis might prove useful for future efforts to design new drugs to be used for mast cell-associated diseases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 64 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 13
Pathology, mast cell, SCF, IL-3, FcεRI, migration, apoptosis, Bim, Bcl-2, Bcl-XL, Akt, FOXO, MAPK, Patologi
National Category
Cell and Molecular Biology
urn:nbn:se:uu:diva-4807 (URN)91-554-6160-3 (ISBN)
Public defence
2005-04-01, Rudbecksalen, Rudbecklaboratoriet, Uppsala, 13:00
Available from: 2005-03-11 Created: 2005-03-11Bibliographically approved

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