NORMAL AND ONCOGENIC FUNCTIONS OF BCL10

描述：（改编自研究者摘要）t（1;14）（p22;q32）为 一种复发性染色体重排，特异于粘膜相关的 淋巴组织（MALT）淋巴瘤导致BCL 10失调， 含N-末端caspase募集结构域（CARD）的凋亡信号转导 通常促进细胞死亡并激活NF-κ B的蛋白质。虽然 BCL 10诱导死亡和NF-κ B活性的机制很差， 据了解，蛋白质的促凋亡作用部分是由于结合和 富含Ser/Thr的BCL 10 C-末端激活半胱天冬酶原-9， 进行磷酸化。除了过度表达外，来自 t（1;14）阳性MALT肿瘤含有多种突变，大多数导致 在CARD中或CARD的C-端进行截短。BCL 10 CARD截短突变体 不能诱导死亡或激活NF-κ B，而C-末端突变体 截短保留NF-κ B活化但不诱导凋亡。因为 BCL 10促进细胞凋亡，它可能在正常情况下执行肿瘤抑制功能。 通过突变导致的BCL 10促凋亡基因的缺失应赋予生存优势 和组成性NF-κ B激活应该提供两者 抗凋亡和增殖信号。的 这些事件在肿瘤发生中的相对重要性，或者BCL 10突变体是否 具有额外的致癌特性，仍然未知。目标1a 该提案旨在通过以下方式提高对BCL 10在肿瘤发生中作用的理解： 使用Bc 110-null阐明其在细胞死亡调节中的正常功能， 细胞以鉴定需要BCL 10活性的凋亡途径， 评估蛋白质的体内肿瘤抑制能力。 BCL 10相互作用蛋白及其C端功能效应 磷酸化将在目标1b中进行研究，以进一步确定机制 控制BCL 10细胞死亡的基因相变增强特性 将在目标2a中评估各种BCL 10突变，其中询问是否 BCL 10的双等位基因失活是促进肿瘤发生所必需的， 无论是反显性抑制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， 正常BCL 10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 在以前的目标中提出的意见。综合起来，这些研究应该 阐明BCL 10调节细胞凋亡的机制以及BCL 10在细胞凋亡中的作用方式。 BCL 10突变改变死亡调节以促进肿瘤发生。

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.