Regulation and Function of Cyclin D3 in B Cell Subsets

B 细胞亚群中 Cyclin D3 的调控和功能

基本信息

  • 批准号:
    6828110
  • 负责人:
  • 金额:
    $ 41.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-07-01 至 2009-04-30
  • 项目状态:
    已结题

项目摘要

Peritoneal B-1 cells constitute a unique B cell subset, distinguished by numerous phenotypic and functional characteristics. B-1 cells are an important subset to study because they are responsible for the majority of non-immune serum immunoglobulin (Ig), which provides serological protection against a range of microorganisms prior to adaptive immunity. B-1 cells have been implicated in the pathogenesis of autoimmunity and malignant transformation. Notably, B-1 cells represent the cell of origin for human chronic lymphocytic leukemia (CLL). In adult animals B-1 cells are self-renewing, whereas conventional splenic B (B-2) cells are not. This suggests that the regulation of G0/GI-S phase progression differs between B-1 and B-2 cells. We have reported that dramatic functional differences exist between B-1 and B-2 cells in the signals required for S-phase entry. B-1 cells fail to proliferate to anti-lg stimulation, which drives B-2 cells into S phase. Conversely, B-1 cells proliferate in response to phorbol ester (PMA) and do so unusually rapidly, whereas B-2 cell proliferation requires PMA plus calcium ionophore. We have studied the cell cycle response to PMA as a means to understand the regulation of G0/G1-S phase progression in B-1 and, more generally, all B cells. Our work has led to several key findings: (i) cyclin D3 is uniquely positioned to mediate S-phase entry in PMA stimulated B-1 cells; (ii) PMA induces cyclin D3-cdk4 complex assembly in B-1 and B-2 cells, but complexes in the latter are inactive. Similarly, IL-4 induces the assembly of inactive cyclin D3-cdk4 complexes in B-2 cells; and (iii) cdk4 exhibits a distinct phosphorylation profile coincident with inhibition of its kinase activity in PMA-stimulated B-2 cells. The long term objective of this project is to understand the regulation and function of cyclin D3 (and cyclinD3-cdk4 complexes) in B-1 and B-2 cells as an entry point for dissecting important elements that govern restriction point progression and commitment to S-phase entry of all B cells. This will be accomplished through three specific aims. 1. Elucidate the biological role of cyclin D3 in peritoneal B-1 cells; 2. Map the phosphorylation sites on cdk4 in B-2 and B-1 cells; and 3. Elucidate the biological role and regulation of individual phosphoacceptor sites in cdk4. The information developed from this project will elucidate novel principles that govern the regulation of G0/G1-to-S progression in B cells and will be of general applicability to the regulation of cell cycle progression in all mammalian cell types.
腹膜B-1细胞构成了独特的B细胞亚群,以许多表型和功能特征区分。B-1细胞是研究的重要亚群,因为它们负责大部分非免疫血清免疫球蛋白(IG),其在获得性免疫之前提供针对一系列微生物的血清学保护。B-1细胞与自身免疫和恶性转化的发病机制有关。值得注意的是,B-1细胞代表人慢性淋巴细胞白血病(CLL)的起源细胞。在成年动物中,B-1细胞是自我更新的,而传统的脾B(B-2)细胞不是。这表明G 0/GI-S期进展的调节在B-1和B-2细胞之间不同。我们已经报道了在细胞周期中B-1和B-2细胞之间存在显著的功能差异。 进入S阶段所需的信号。B-1细胞不能对抗Ig刺激增殖,这驱使B-2细胞进入S期。相反,B-1细胞响应佛波酯(PMA)增殖,并且增殖速度非常快,而B-2细胞增殖需要PMA加钙离子载体。我们已经研究了细胞周期对PMA的反应,作为理解B-1和更普遍地所有B细胞中G 0/G1-S期进展的调节的手段。我们的工作已经导致了几个关键的发现:(i)细胞周期蛋白D3是唯一的定位,以介导PMA刺激的B-1细胞的S期进入;(ii)PMA诱导细胞周期蛋白D3-cdk 4复合物组装在B-1和B-2细胞,但后者中的复合物是无活性的。类似地,IL-4诱导B-2细胞中无活性的细胞周期蛋白D3-cdk 4复合物的组装;和(iii)cdk 4表现出与其磷酸化抑制相一致的独特磷酸化特征。 PMA刺激的B-2细胞中的激酶活性。本项目的长期目标是了解细胞周期蛋白D3(和细胞周期蛋白D3-cdk 4复合物)在B-1和B-2细胞中的调节和功能,作为解剖所有B细胞限制点进展和进入S期的重要因素的切入点。这将通过三个具体目标来实现。1.阐明细胞周期蛋白D3在腹膜B-1细胞中的生物学作用; 2.绘制B-2和B-1细胞中cdk 4上的磷酸化位点;和3.阐明cdk 4中个别磷酸受体位点的生物学作用及调控。信息来源于 该项目将阐明控制B细胞中G 0/G1-到-S进程的调节的新原理,并将普遍适用于所有哺乳动物细胞类型中细胞周期进程的调节。

项目成果

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Thomas C. Chiles其他文献

Influence of nitrogen availability on agar-polysaccharides fromGracilaria verrucosa strain G-16: structural analysis by NMR spectroscopy
  • DOI:
    10.1007/bf00003535
  • 发表时间:
    1989-04-01
  • 期刊:
  • 影响因子:
    3.000
  • 作者:
    Thomas C. Chiles;Kimon T. Bird;Frank E. Koehn
  • 通讯作者:
    Frank E. Koehn
<em>Thematic Review Series: Sphingolipids.</em> Ganglioside GM3 suppresses the proangiogenic effects of vascular endothelial growth factor and ganglioside GD1a
  • DOI:
    10.1194/jlr.m800002-jlr200
  • 发表时间:
    2008-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Purna Mukherjee;Anthony C. Faber;Laura M. Shelton;Rena C. Baek;Thomas C. Chiles;Thomas N. Seyfried
  • 通讯作者:
    Thomas N. Seyfried

Thomas C. Chiles的其他文献

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{{ truncateString('Thomas C. Chiles', 18)}}的其他基金

National Research Mentoring Network for a Diverse Biomedical Workforce
多元化生物医学劳动力的国家研究指导网络
  • 批准号:
    9062629
  • 财政年份:
    2014
  • 资助金额:
    $ 41.55万
  • 项目类别:
National Research Mentoring Network for a Diverse Biomedical Workforce
多元化生物医学劳动力的国家研究指导网络
  • 批准号:
    9062630
  • 财政年份:
    2014
  • 资助金额:
    $ 41.55万
  • 项目类别:
Glucose energy metabolism in the growth and survival of B lymphocytes
B 淋巴细胞生长和存活中的葡萄糖能量代谢
  • 批准号:
    7652102
  • 财政年份:
    2009
  • 资助金额:
    $ 41.55万
  • 项目类别:
Glucose energy metabolism in the growth and survival of B lymphocytes
B 淋巴细胞生长和存活中的葡萄糖能量代谢
  • 批准号:
    7843495
  • 财政年份:
    2009
  • 资助金额:
    $ 41.55万
  • 项目类别:
Role of Cdc37 in FcyR-induced Growth Arrest in B Cells
Cdc37 在 FcyR 诱导的 B 细胞生长停滞中的作用
  • 批准号:
    6895092
  • 财政年份:
    2002
  • 资助金额:
    $ 41.55万
  • 项目类别:
Role of Cdc37 in FcyR-induced Growth Arrest in B Cells
Cdc37 在 FcyR 诱导的 B 细胞生长停滞中的作用
  • 批准号:
    6747552
  • 财政年份:
    2002
  • 资助金额:
    $ 41.55万
  • 项目类别:
Role of Cdc37 in FcyR-induced Growth Arrest in B Cells
Cdc37 在 FcyR 诱导的 B 细胞生长停滞中的作用
  • 批准号:
    6623658
  • 财政年份:
    2002
  • 资助金额:
    $ 41.55万
  • 项目类别:
Role of Cdc37 in FcyR-induced Growth Arrest in B Cells
Cdc37 在 FcyR 诱导的 B 细胞生长停滞中的作用
  • 批准号:
    6469161
  • 财政年份:
    2002
  • 资助金额:
    $ 41.55万
  • 项目类别:
Cdc37 in Fcgamma R-induced Growth Arrest in B Cells
Fcgamma R 诱导的 B 细胞生长停滞中的 Cdc37
  • 批准号:
    6359190
  • 财政年份:
    2001
  • 资助金额:
    $ 41.55万
  • 项目类别:
REGULATION AND FUNCTION OF AP-1 IN PRIMARY B-CELLS
原代 B 细胞中 AP-1 的调节和功能
  • 批准号:
    2069746
  • 财政年份:
    1993
  • 资助金额:
    $ 41.55万
  • 项目类别:

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