NORMAL AND ONCOGENIC FUNCTIONS OF BCL10

BCL10 的正常功能和致癌功能

• 批准号: 6377990
• 负责人: STEPHAN W MORRIS
• 金额: $ 33.32万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377990
• 关键词: alleles; apoptosis; chromosome translocation; complementary DNA; cysteine endopeptidases; gene mutation; genetic transcription; genetically modified animals; laboratory mouse; neoplasm /cancer genetics; nonHodgkin's lymphoma; nuclear factor kappa beta; oncoproteins; phosphoproteins; phosphorylation; tumor suppressor proteins; yeast two hybrid system

DESCRIPTION: (adapted from the investigator's abstract) The t(1;14)(p22;q32) is a recurrent chromosomal rearrangement specific to the mucosa-associated lymphoid tissue (MALT) lymphomas that results in dysregulation of BCL10, an N-terminal caspase recruitment domain (CARD)-containing apoptosis signaling protein that normally promotes cell death and activates NF-kappaB. Although the mechanisms by which BCL10 induces death and NF-kappaB activity are poorly understood, proapoptosis by the protein appears due in part to binding and activation of procaspase-9 by the Ser/Thr-rich BCL10 C-terminus, which can undergo phosphorylation. In addition to being overexpressed, BCL10 cDNAs from t(1;14)-positive MALT tumors contain a variety of mutations, most resulting in truncations either in or C-termnal to the CARD. BCL10 CARD-truncation mutants are unable to induce death or activate NF-kappaB, while mutants with C-terminal truncations retain NF-kappaB activation but do not induce apoptosis. Because BCL10 promotes apoptosis, it may normally perform a tumor suppressor function. Loss of BCL10 proapoptosis through mutation should confer a survival advantage to cells, and constitutive NF-kappaB activation should provide both antiapoptotic and proliferative signals via its transcriptional targets. The relative importance of these events in tumorigenesis, or whether BCL10 mutants possess additional oncogenic properties, remain unknown. Aim 1a of this proposal seeks to improve understanding of the role of BCL10 in oncogenesis by elucidating its normal function in cell death regulation, using Bc110-null cells to identify the apoptotic pathways that require BCL10 activity and assessing the tumor suppressor capabilities of the protein in vivo. BCL10-interacting proteins and the functional effects of BCL10 C-terminal phosphorylation will be investigated in Aim 1b to further define the mechanisms that govern BCL10 cell death control. The transformation-enhancing properties of various BCL10 mutations will be assessed in Aim 2a, which asks whether biallelic inactivation of BCL10 is required for promotion of oncogenesis, and whether transdominant-inhibitory or transforming gain-of-function monoallelic mutations also contribute to tumor development. Finally, in Aim 2b, the effects of normal BCL10 or selected mutants on lymphoid development and transformation will be assessed in transgenic mice models to ensure the biologic relevance of observations made in previous Aims. Taken together, these studies should clarify the mechanisms by which BCL10 regulates apoptosis and the manner in which BCL10 mutations alter death regulation to promote oncogenesis.

描述：（改编自研究者的摘要）t(1;14)(p22;q32) 是 与粘膜相关的特异性的反复染色体重排 淋巴组织 (MALT) 淋巴瘤导致 BCL10 失调，BCL10 是一种 含有 N 端半胱天冬酶募集结构域 (CARD) 的细胞凋亡信号传导 通常促进细胞死亡并激活 NF-kappaB 的蛋白质。虽然 BCL10 诱导死亡和 NF-κB 活性的机制尚不明确 据了解，该蛋白质的促凋亡部分是由于结合和 富含 Ser/Thr 的 BCL10 C 末端激活 procaspase-9，这可以 进行磷酸化。除了过度表达之外，BCL10 cDNA 还来自 t(1;14) 阳性 MALT 肿瘤包含多种突变，大多数导致 CARD 内或 C 端的截断。 BCL10 CARD 截短突变体 不能诱导死亡或激活 NF-κB，而具有 C 末端的突变体 截短保留 NF-kappaB 激活但不诱导细胞凋亡。因为 BCL10促进细胞凋亡，它通常可以发挥抑癌功能。 通过突变导致 BCL10 促凋亡的丧失应该会带来生存优势 NF-kappaB 的组成型激活应提供 通过其转录靶点产生抗凋亡和增殖信号。这 这些事件在肿瘤发生中的相对重要性，或者 BCL10 突变体是否 具有额外的致癌特性，但仍未知。目标 1a 该提案旨在通过以下方式增进对 BCL10 在肿瘤发生中作用的理解： 使用 Bc110-null 阐明其在细胞死亡调节中的正常功能 细胞识别需要 BCL10 活性的细胞凋亡途径， 评估蛋白质在体内的肿瘤抑制能力。 BCL10 相互作用蛋白和 BCL10 C 末端的功能效应 将在目标 1b 中研究磷酸化，以进一步明确其机制 控制 BCL10 细胞死亡控制。促进转化的特性 各种 BCL10 突变将在目标 2a 中进行评估，该问题询问是否 BCL10 的双等位基因失活是促进肿瘤发生所必需的，并且 无论是反显性抑制型还是转化功能获得性单等位基因 突变也有助于肿瘤的发展。最后，在目标 2b 中，效果 正常 BCL10 或选定突变体对淋巴发育和转化的影响 将在转基因小鼠模型中进行评估，以确保其生物学相关性 先前目标中所做的观察。综合起来，这些研究应该 阐明BCL10调节细胞凋亡的机制及其方式 BCL10 突变改变死亡调节以促进肿瘤发生。