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
• 负责人: Thomas C. Chiles
• 金额: $ 26.55万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6359190
• 关键词: B cell receptor; B lymphocyte; antibody receptor; cell cycle; cell cycle proteins; cell growth regulation; cyclin dependent kinase; cyclins; laboratory mouse; mass spectrometry; phosphorylation; receptor coupling

DESCRIPTION (provided by applicant): The long-term objective of this new application is to understand how engagement of the B-cell antigen receptor (BCR), simultaneously with the Ig receptor (FcgammaRIIB), inhibits B-cell proliferation. Loss of FcgammaRIIB function can lead to autoantibody production and may contribute to autoimmune disease. Therefore, understanding the molecular basis that underlies growth arrest has significant implications for both humoral immune responses and pathology associated with FcgammaRIIB dysregulation. The D-type cyclin/cyclin dependent kinase(cdk) 4-retinoblastoma (pRb) pathway is a primary target for growth factor signals and functions to regulate G1-to-S phase progression. Our results indicate that BCR-FcgammaRIIB co-cross-linking exerts its growth inhibitory effect, in part, by signaling the phosphorylation of Cdc37. Cdc37, along with hsp9O, plays an essential role in the pathway leading to D-type cyclin-cdk4 complex assembly. The research proposed herein will test the hypotheses that phosphorylation of Cdc37 in response to BCR-FcgammaRIIB coengagement: a) prevents targeting of hsp9O/Cdc37 to cdk4; b) blocks assembly of D-type cyclin kinase complexes; and c) promotes growth arrest in mature B lymphocytes. These hypotheses will be tested in three specific aims that include: 1) mass spectrometry to identify BCR-FcgammaRIIB-inducible phosphoacceptor sites on Cdc37; 2) in vitro binding assays and in vivo ectopic expression of alanine point-mutated GSTCdc37, that cannot be phosphorylated by negative signals, will be used to evaluate the role of phosphorylation on targeting of hsp9O/Cdc37 to cdk4 and in D-type cyclin kinase assembly; and 3) ectopic expression of aspartic acid substituted FLAG-Cdc37 will be used to mimic phosphorylation and force the disruption of D-type cyclin kinase complexes and promote growth arrest. The information obtained from these studies will serve to direct future studies aimed at therapeutic interventions in autoimmune disease.

描述(由申请人提供)：这项新计划的长期目标 其应用是了解B细胞抗原受体如何参与 (BCR)与Ig受体(FcGammaRIIB)同时抑制B细胞 扩散。FcGammaRIIB功能缺失可导致自身抗体产生 并可能导致自身免疫性疾病。因此，理解 生长停滞背后的分子基础对 FcGammaRIIB的体液免疫反应和病理改变 监管失调。D型细胞周期蛋白/细胞周期蛋白依赖性激酶4-视网膜母细胞瘤 (PRB)途径是生长因子信号和功能的主要靶点 调节G1期向S期的进程。我们的结果表明，BCR-FcGammaRIIB 共交联剂发挥其生长抑制作用，部分是通过信号转导 CDC37的磷酸化。Cdc37与hsp9O一起在 导致D型细胞周期蛋白-CDK4复合体组装的途径。这项研究 在这里提出的将检验假设的CDC37的磷酸化 对bcr-FcGammaRIIB共参与的反应：a)阻止靶向hsp90/cdc37 对CDK4的作用；b)阻断D型细胞周期蛋白激酶复合体的组装；以及c)促进 成熟B淋巴细胞的生长停滞。这些假说将在三个方面进行检验 具体目标包括：1)质谱学鉴定 CDC37上BCR-FcGammaRIIB诱导的磷受体位点；2)体外结合 丙氨酸点突变的GSTCDC37的检测和体内异位表达 不能被负面信号磷酸化，将被用来评估作用 Hsp90/CDC37靶向CDK4和D型细胞周期蛋白的磷酸化研究 3)天冬氨酸取代的异位表达 FLAG-CDC37将被用来模拟磷酸化并强制破坏 D-型细胞周期蛋白激酶复合体，促进生长停滞。这些信息 从这些研究中获得的结果将有助于指导未来旨在 自身免疫性疾病的治疗干预。

项目成果

Resveratrol induces apoptosis in transformed follicular lymphoma OCI-LY8 cells: evidence for a novel mechanism involving inhibition of BCL6 signaling.

白藜芦醇诱导转化滤泡性淋巴瘤 OCI-LY8 细胞凋亡：涉及抑制 BCL6 信号传导的新机制的证据。

• 发表时间: 2006
• 期刊: International journal of oncology
• 影响因子: 5.2
• 作者: Faber,AnthonyC;Chiles,ThomasC
• 通讯作者: Chiles,ThomasC