Control of hematopoietic cell differentiation by c-Fos and Bcl6

c-Fos 和 Bcl6 对造血细胞分化的控制

• 批准号: 13671047
• 负责人: OKADA Seiji
• 金额: $ 2.56万
• 依托单位: Kumamoto University (2002)Chiba University (2001)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671047/
• 关键词: c-Fos; Bcl6; Differentiation; macrophage; Memory B cell; C-fos; 造血幹細胞; BCL6; BAZF; 転写抑制; B細胞

Proliferation and differentiation of hematologic cells are regulated by transcriptional factors. We have analyzed role of two immediated early genes, c-Fos and Bcl6.c-Fos forms AP-1 complex with Jun family and regulates the expression of AP-1 binding genes. Expression of c-fos is induced in normal myelopoiesis. To explore the function of c-fos on myeloid differentiation, we used the murine myeloblastic leukemia cell line M1. Stimulation of M1 cells with LPS promotes their terminal differentiation into functional macrophages. Overexpression of c-fos in M1 cells dramatically increased sensitivity of the cells for LPS-induced differentiation and generation of morphologically differentiated cells. However, the overexpression did not modulate phagocytotic functions, surface expression of macrophage markers such as CD16/CD32 (FcgR) and CD54 (ICAM-1), and expression of lysozyme, esterase and c-fins mRNA. Induction of the class II MHC expression on M1 cells after stimulation was inhibited by t … More he overexpression. Expression of CIITA was also reduced in the M1 cells. Overexpression of c-fos in differentiating M1 cells perturbs their functional maturation.The Bcl6 gene has been identified from the chromosomal translocation breakpoint in B-cell lymphoma and its product functions as a sequence-specific transcriptional repressor. After immunization with T cell-dependent antigens, the high-affinity B cells selected in germinal centers differentiate into memory B cells or long-lived antibody forming cells. We showed that Bcl6-deficient B cells, which cannot develop germinal centers, differentiated into IgM and IgG1 memory B cells but barely into long-lived IgG1 antibody forming cells in the bone marrow. Mutation in the V-heavy gene was nil in these memory B cells. Bcl6 and germinal center formation are essential for somatic hypermutation and affinity maturation, and generation of memory B cells can occur independent of germinal center formation, Ig class-switching and affinity maturation. Less

血液细胞的增殖和分化受转录因子的调控。我们分析了两个直接早期基因c-Fos和bcl6的作用，c-Fos与Jun家族形成AP-1复合物，调控AP-1结合基因的表达。c-fos在正常骨髓形成中被诱导表达。为了探讨c-fos对髓细胞分化的作用，我们以小鼠成髓细胞白血病细胞系M1为研究对象。LPS刺激M1细胞可促进其向功能性巨噬细胞的终端分化。c-fos在M1细胞中的过表达显著增加了细胞对lps诱导的分化和形态分化细胞的敏感性。然而，过表达不影响吞噬功能、巨噬细胞表面标志物CD16/CD32 （FcgR）和CD54 （ICAM-1）的表达以及溶菌酶、酯酶和c-fins mRNA的表达。刺激后M1细胞ⅱ类MHC表达的诱导被t…M1细胞中CIITA的表达也降低。c-fos在分化M1细胞中的过度表达会干扰其功能成熟。Bcl6基因已从b细胞淋巴瘤的染色体易位断点中鉴定出来，其产物作为序列特异性转录抑制因子发挥作用。在T细胞依赖抗原免疫后，生发中心选择的高亲和力B细胞分化为记忆B细胞或长寿命抗体形成细胞。我们发现，缺乏bcl6的B细胞不能发育生发中心，在骨髓中分化为IgM和IgG1记忆B细胞，但很少分化为长寿命的IgG1抗体形成细胞。在这些记忆B细胞中，重v基因的突变为零。Bcl6和生发中心的形成对体细胞超突变和亲和成熟至关重要，记忆B细胞的产生可以独立于生发中心的形成、Ig类转换和亲和成熟而发生。少

项目成果

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