title: Regulation of mast cell survival and function by tuberous sclerosis complex 1.
abstract: 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.
authors.affiliation: Department of Pediatrics-Division of Allergy and Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jinwook
authors.initials: J
authors.lastname: Shin
authors.forename: Hongjie
authors.initials: H
authors.lastname: Pan
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D015550:Cell Degranulation / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D015870:Gene Expression; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics; D046912:Multiprotein Complexes; D011506:Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D000077004:Tuberous Sclerosis Complex 1 Protein; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C504923:Crtc2 protein, mouse; D016207:Cytokines; C501470:FcRI protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D046912:Multiprotein Complexes; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; C000624650:TSC1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D007073:Immunoglobulin E; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases