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Mol Cell Biol. 2017 Nov 28;37(24). pii: e00418-17. doi: 10.1128/MCB.00418-17. Print 2017 Dec 15.

The mTOR-Bach2 Cascade Controls Cell Cycle and Class Switch Recombination during B Cell Differentiation.

Author information

1
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
2
Department of Preventive Dentistry, Tohoku University Graduate School of Dentistry, Sendai, Japan.
3
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan kochiai@med.tohoku.ac.jp igarashi@med.tohoku.ac.jp.
4
New Industry Creation Hatchery Center, Tohoku University, Sendai, Japan.
5
Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan.
6
Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan.

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.

KEYWORDS:

B cells; cell cycle; immunoglobulin gene rearrangement; mTOR; transcription factor

PMID:
28993481
PMCID:
PMC5705818
DOI:
10.1128/MCB.00418-17
[Indexed for MEDLINE]
Free PMC Article

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