Role of OCA-B in B cell differentiation and malignancy

OCA-B 在 B 细胞分化和恶性肿瘤中的作用

• 批准号: 7047816
• 负责人: ROBERT G ROEDER
• 金额: $ 51.7万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7047816
• 关键词: B cell lymphoma; B lymphocyte; carcinogenesis; cell differentiation; chromatin; fatty acylation; genetic enhancer element; genetic promoter element; immunogenetics; immunoglobulin genes; laboratory mouse; leukocyte activation /transformation; myristates; protein isoforms; protein purification; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): B cell differentiation and function (antibody production) is regulated through the programmed expression and function of transcription factors on specific genes in response to various stimuli; and alterations in these programs and in the genetic targets (e.g. immunoglobulin [Ig] gene loci) can lead to various malignancies. The B cell-specific transcriptional coactivator OCA-B was identified biochemically on the basis of its ability to activate Ig gene transcription through interactions with promoter-bound OCT factors. Subsequent gene targeting studies showed that OCA-B is essential both for antigen-dependent B cell differentiation, including germinal center (GC) formation, and for normal expression of secondary Ig isotypes, but not for Ig transcription in early B cell differentiation. These observations suggested the presence not only of other (non-lg) target genes but also of another coactivator for OCT-dependent transcription of Ig genes in early B cells. The critical role of OCA-B in GC formation, along with the presence of many lymphoid malignancies of GC origin, underscores the importance of understanding OCA-B functions and mechanisms. The long-term objective is to study how OCA-B regulates critical B cell differentiation events, through different target genes, in health and disease. Based on recent developments, and using integrated biochemical, cell biological and mouse gene targeting approaches, our specific objectives are (i) to biochemically purify and functionally characterize a newly-identified B cell-specific OCT coactivator activity (OCA-B2) that could be partially redundant with OCA-B, (ii) to detail the mechanism of action of OCA-B, through interactions with the general transcriptional machinery and chromatin remodeling factors, in effecting Ig promoter and enhancer function and synergy, (iii) to elucidate the role of newly identified non-lg OCA-B target genes in B cell differentiation, (iv) to determine the specific (potentially distinct) functions of the nuclear p34 and myristoylated plasma membrane/nuclear p35 isoforms of OCA-B, as well as a potentially novel cytoplasmic-nuclear signaling pathway for OCA-B/p35 in response to B cell receptor (BCR) engagement and (v) to develop a mouse model to investigate the role of OCA-B in the function of the translocated IgH 3' enhancer in B cell lymphomas.

描述（由申请人提供）：B细胞分化和功能（抗体产生）通过特定基因上转录因子的程序化表达和功能来调节，以响应各种刺激;这些程序和遗传靶点（例如免疫球蛋白[IG]基因座）的改变可导致各种恶性肿瘤。B细胞特异性转录共激活因子OCA-B是根据其通过与启动子结合的OCT因子相互作用激活IG基因转录的能力进行生物化学鉴定的。随后的基因靶向研究表明，OCA-B是抗原依赖性B细胞分化，包括生发中心（GC）的形成，并为第二IG同种型的正常表达，但不是在早期B细胞分化的IG转录所必需的。这些观察结果表明，在早期B细胞中，不仅存在其他（非Ig）靶基因，而且还存在另一种用于IG基因的OCT依赖性转录的共激活因子。OCA-B在GC形成中的关键作用，沿着许多GC起源的淋巴恶性肿瘤的存在，强调了理解OCA-B功能和机制的重要性。长期目标是研究OCA-B如何通过不同的靶基因调节健康和疾病中的关键B细胞分化事件。基于最近的发展，并使用整合的生物化学、细胞生物学和小鼠基因靶向方法，我们的具体目标是（i）生物化学纯化和功能表征新鉴定的B细胞特异性OCT共激活因子活性（OCA-B2），其可能与OCA-B部分冗余，（ii）详细描述OCA-B的作用机制，通过与一般转录机制和染色质重塑因子的相互作用，影响IG启动子和增强子的功能和协同作用，（iii）阐明新鉴定的非Ig OCA-B靶基因在B细胞分化中的作用，（四）确定具体OCA-B的核p34和豆蔻酰化质膜/核p35同种型的（可能不同的）功能，以及OCA-B/p35响应于B细胞受体（BCR）接合的潜在的新的细胞质-核信号传导途径，以及（v）开发小鼠模型以研究OCA-B/p35的作用。B在B细胞淋巴瘤中IgH 3'端增强子易位的功能