Regulation of mast cell survival and function by tuberous sclerosis complex 1.
Mast cells play critical roles in allergic disorders and asthma. The importance of tuberous sclerosis complex 1/2-mammalian target of rapamycin (TSC1/2-mTOR) signaling in mast cells is unknown. Here, we report that TSC1 is a critical regulator for mTOR signaling in mast cells downstream of FcεRI and c-Kit, and differentially controls mast cell degranulation and cytokine production. TSC1-deficiency results in impaired mast cell degranulation, but enhanced cytokine production in vitro and in vivo after FcεRI engagement. Furthermore, TSC1 is critical for mast cell survival through multiple pathways of apoptosis including the down-regulation of p53, miR-34a, reactive oxygen species, and the up-regulation of Bcl-2. Together, these findings reveal that TSC1 is a critical regulator of mast cell activation and survival, suggesting the manipulation of the TSC1/2-mTOR pathway as a therapeutic strategy for mast cell-mediated diseases.
Duke Scholars
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Related Subject Headings
- Tumor Suppressor Proteins
- Tumor Suppressor Protein p53
- Tuberous Sclerosis Complex 1 Protein
- Transcription Factors
- Trans-Activators
- TOR Serine-Threonine Kinases
- Signal Transduction
- Reactive Oxygen Species
- Proto-Oncogene Proteins c-bcl-2
- Proto-Oncogene Proteins c-akt
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Tumor Suppressor Proteins
- Tumor Suppressor Protein p53
- Tuberous Sclerosis Complex 1 Protein
- Transcription Factors
- Trans-Activators
- TOR Serine-Threonine Kinases
- Signal Transduction
- Reactive Oxygen Species
- Proto-Oncogene Proteins c-bcl-2
- Proto-Oncogene Proteins c-akt