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The mTOR-Bach2 Cascade Controls Cell Cycle and Class Switch Recombination during B Cell Differentiation.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2017 Nov 28; Vol. 37 (24). Date of Electronic Publication: 2017 Nov 28 (Print Publication: 2017). - Publication Year :
- 2017
-
Abstract
- 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.<br /> (Copyright © 2017 American Society for Microbiology.)
- Subjects :
- Animals
Basic-Leucine Zipper Transcription Factors genetics
Cell Cycle physiology
Cell Differentiation physiology
Cyclin D3 metabolism
Mice
Mice, Knockout
Morpholines pharmacology
Recombination, Genetic
TOR Serine-Threonine Kinases antagonists & inhibitors
TOR Serine-Threonine Kinases genetics
B-Lymphocytes cytology
B-Lymphocytes metabolism
Basic-Leucine Zipper Transcription Factors metabolism
TOR Serine-Threonine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5549
- Volume :
- 37
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 28993481
- Full Text :
- https://doi.org/10.1128/MCB.00418-17