期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 37, 期 24, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00418-17
关键词
B cells; cell cycle; immunoglobulin gene rearrangement; mTOR; transcription factor
资金
- Ministry of Education, Science, Sport, and Culture of Japan [KAKENHI 16K15227, 15H02506, 24390066, 16K19026, 16H01295]
- AMED-CREST
- Astellas Foundation for Research on Metabolic Disorders
- Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]) from AMED from Japan Agency for Medical Research and development, AMED
- Grants-in-Aid for Scientific Research [16K19026, 24390066, 16H01295, 16K07108, 15K15771, 15H02506] Funding Source: KAKEN
The transcription factor Bach2 regulates both acquired and innate immunity at multiple steps, including antibody class switching and regulatory T cell development in activated B and T cells, respectively. However, little is known about the molecular mechanisms of Bach2 regulation in response to signaling of cytokines and antigen. We show here that mammalian target of rapamycin (mTOR) controls Bach2 along B cell differentiation with two distinct mechanisms in pre-B cells. First, mTOR complex 1 (mTORC1) inhibited accumulation of Bach2 protein in nuclei and reduced its stability. Second, mTOR complex 2 (mTORC2) inhibited FoxO1 to reduce Bach2 mRNA expression. Using expression profiling and chromatin immunoprecipitation assay, the Ccnd3 gene, encoding cyclin D3, was identified as a new direct target of Bach2. A proper cell cycle was lost at pre-B and mature B cell stages in Bach2-deficient mice. Furthermore, AZD8055, an mTOR inhibitor, increased class switch recombination in wild-type mature B cells but not in Bach2-deficient cells. These results suggest that the mTOR-Bach2 cascade regulates proper cell cycle arrest in B cells as well as immunoglobulin gene rearrangement.
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