NORMAL AND ONCOGENIC FUNCTIONS OF BCL10

描述：(改编自调查人员的摘要)t(1；14)(p22；q32)是 一种反复发生的染色体重排，专属于粘膜相关的 淋巴组织(MALT)淋巴瘤，导致Bcl10，And N-末端caspase募集结构域(CARD)含细胞凋亡信号 正常情况下促进细胞死亡并激活核因子-kappaB的蛋白质。尽管 Bcl10诱导死亡和核因子-kappaB活性的机制很差 理解，蛋白质的促细胞凋亡似乎部分是由于结合和 由富含丝氨酸/苏氨酸的Bcl10 C-末端激活原天冬氨酸酶-9，它可以 进行磷酸化。除了过度表达外，Bcl10 cDNA来自 T(1；14)阳性的MALT肿瘤包含各种突变，大多数导致 卡中或C-Term中的截断。Bcl10卡截断突变体 不能诱导死亡或激活核因子-kappaB，而带有C-末端的突变体 截断保留了核因子-kappaB的激活，但不会诱导细胞凋亡。因为 Bcl10可促进细胞凋亡，正常情况下可能具有肿瘤抑制作用。 通过突变失去bcl10促细胞凋亡应该会带来生存优势 和结构性的核因子-kappaB激活应提供 通过其转录靶点的抗细胞凋亡和增殖信号。这个 这些事件在肿瘤发生中的相对重要性，或者Bcl10突变 具有额外的致癌特性，目前尚不清楚。这方面的目标1a 该提案旨在通过以下方式提高对Bcl10在肿瘤发生中的作用的理解 利用Bc110-空基因阐明其在细胞死亡调控中的正常功能 细胞识别需要Bcl10活性的凋亡通路，并 在体内评估该蛋白质的肿瘤抑制能力。 Bcl10相互作用蛋白及其C末端的功能效应 目标1b将对磷酸化进行研究，以进一步确定其机制。 管理Bcl10细胞死亡控制的机构。相变增强性质 在目标2a中将对各种bcl10突变进行评估，该目标询问 Bcl10的双等位基因失活是促进肿瘤发生所必需的，并且 无论是跨显性抑制型还是转换型功能增益单等位基因 突变也有助于肿瘤的发展。最后，在目标2b中，影响 正常Bcl10或突变体对淋巴系发育和转化的影响 将在转基因小鼠模型中进行评估，以确保 在以前的目标中所做的观察。总而言之，这些研究应该 阐明Bcl10调控细胞凋亡的机制和途径 哪些Bcl10突变改变了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.