The Tumor Suppression Potential of NF-kappaB2 p100

描述（由申请人提供）：该项目的长期目标是了解NF-(B2)基因的遗传改变如何导致肿瘤发生。NF-kappaBeta2基因编码一个约100 kda （p100）的蛋白，可通过其c端死亡结构域和/或lkappaB活性促进细胞凋亡。在对某些信号的响应中，p100被加工产生一个52-kDa的转录因子（p52），该转录因子对应于p100的n端一半。p52的异常激活已在乳腺癌中被观察到。此外，NF-kappaB2基因的c端缺失和重排在多种B细胞和t细胞淋巴瘤中反复发生。这些遗传改变的一个基本特征是产生具有致癌潜力的c端截断NF-kappaB2突变体和p100作为凋亡蛋白的失活。我们最近的研究表明，p100在胸腺细胞中是tnf - α和激活诱导的凋亡的关键调节剂，并且在细胞和动物中是肿瘤来源的NF-kappaB2突变体p80HT的致癌活性抑制剂。这些发现使我们假设p100是一种促进细胞凋亡的肿瘤抑制因子，并作为NF-kappaB2的致癌突变和p52的异常激活的内置防御。我们将在细胞和动物系统中测试这一假设。在基于动物的研究中（Aim 1），我们将在淋巴细胞中靶向表达p80HT或p52的转基因小鼠中建立p100作为抗淋巴瘤形成的肿瘤抑制因子；我们将研究NF-kappaB2 p100基因在这些小鼠模型中单倍体抑制肿瘤的可能性；p100作为一般肿瘤抑制因子的潜力将在E/mu-myc转基因小鼠中进行评估。在基于细胞的研究中（Aim 2），我们将使用骨髓细胞转化作为读数来定义p100的生化活性，p100的抗肿瘤功能和p100抑制肿瘤转化的凋亡途径是必不可少的；我们将对具有明确NF-kappaB2突变的动物淋巴细胞和淋巴瘤细胞的凋亡反应进行表征，以在分子水平上确定与淋巴瘤发生相关的凋亡调节缺陷；我们将使用胸腺激活诱导的细胞凋亡作为模型来描述p100作为凋亡蛋白的分子机制。这些研究可能会定义一类新的肿瘤抑制因子，它们可以作为一种监测机制来对抗自身基因的致癌突变。

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand how genetic alterations of the NF-(B2 gene may lead to tumorigenesis. The NF-kappaBeta2 gene encodes a protein of approximately 100-kDa (p100) that can promote apoptosis via its C-terminal death domain and/or lkappaB activity. In response to certain signals, p100 is processed to generate a 52-kDa transcriptional factor (p52) corresponding to the N-terminal half of p100. Aberrant activation of p52 has been observed in breast cancers. Also, C-terminal deletions and rearrangements of the NF-kappaB2 gene occur recurrently in a variety of B- and T-cell lymphomas. A fundamental feature of these genetic alterations is the generation of C-terminally truncated NF-kappaB2 mutants with oncogenic potential and the inactivation of p100 as an apoptotic protein. Our recent work suggests that p100 is a crucial regulator of TNF-alpha- and activation-induced apoptosis in thymocytes, and an inhibitor of the oncogenic activity of the tumor-derived NF-kappaB2 mutant p80HT in cells and in animals. These findings lead us to hypothesize that p100 is a tumor suppressor that promotes apoptosis and acts as a built-in defense against oncogenic mutations of NF-kappaB2 and aberrant activation of p52. We will test this hypothesis in both cell- and animal-based systems. In animal-based studies (Aim 1), we will establish p100 as a tumor suppressor against lymphomagenesis in transgenic mice with targeted expression of p80HT or p52 in lymphocytes; we will examine the possibility that the NF-kappaB2 p100 gene is haplo-insufficient for tumor suppression in these mouse models; the potential of p100 as a general tumor suppressor will be assessed in E/mu-myc transgenic mice. In cell-based studies (Aim 2), we will use bone marrow cell transformation as readout to define the biochemical activity of p100 essential for its anti-oncogenic function and the apoptotic pathway through which p100 suppresses oncogenic transformation; we will characterize apoptotic responses in lymphocytes and lymphoma cells from the animals with defined NF-kappaB2 mutations to identify at molecular levels the defects in apoptosis regulation that are linked to lymphomagenesis; we will use thymic activation-induced apoptosis as a model to delineate the molecular mechanism for p100 as an apoptotic protein. These studies may define a new class of tumor suppressors that act as a surveillance mechanism against oncogenic mutations of their own genes.