Title | Sin1-mTORC2 suppresses rag and il7r gene expression through Akt2 in B cells. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Lazorchak AS, Liu D, Facchinetti V, Di Lorenzo A, Sessa WC, Schatz DG, Su B |
Journal | Mol Cell |
Volume | 39 |
Issue | 3 |
Pagination | 433-43 |
Date Published | 2010 Aug 13 |
ISSN | 1097-4164 |
Keywords | Adaptor Proteins, Signal Transducing, Animals, B-Lymphocytes, Cell Line, Transformed, DNA-Binding Proteins, Forkhead Box Protein O1, Forkhead Transcription Factors, Gene Expression Regulation, Gene Rearrangement, B-Lymphocyte, Homeodomain Proteins, Mice, Mice, Knockout, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptors, Interleukin-7, Signal Transduction, TOR Serine-Threonine Kinases, Transcription Factors |
Abstract | Mammalian target of rapamycin (mTOR) is an important mediator of phosphoinositol-3-kinase (PI3K) signaling. PI3K signaling regulates B cell development, homeostasis, and immune responses. However, the function and molecular mechanism of mTOR-mediated PI3K signaling in B cells has not been fully elucidated. Here we show that Sin1, an essential component of mTOR complex 2 (mTORC2), regulates B cell development. Sin1 deficiency results in increased IL-7 receptor (il7r) and RAG recombinase (rag1 and rag2) gene expression, leading to enhanced pro-B cell survival and augmented V(D)J recombinase activity. We further show that Akt2 specifically mediates the Sin1-mTORC2 dependent suppression of il7r and rag gene expression in B cells by regulating FoxO1 phosphorylation. Finally, we demonstrate that the mTOR inhibitor rapamycin induces rag expression and promotes V(D)J recombination in B cells. Our study reveals that the Sin1/mTORC2-Akt2 signaling axis is a key regulator of FoxO1 transcriptional activity in B cells. |
DOI | 10.1016/j.molcel.2010.07.031 |
Alternate Journal | Mol Cell |
PubMed ID | 20705244 |
PubMed Central ID | PMC2957800 |
Grant List | AI 063348 / AI / NIAID NIH HHS / United States |
Related Lab:
Related Faculty:
Annarita Di Lorenzo, Ph.D.