NF-kB Signaling & Molec Pathogenesis of MALT Lymphoma

核因子-kappaB转录因子最近被认为是细胞命运的关键调节因子。在大多数情况下，核因子-kappaB刺激一系列促进细胞存活和增殖的基因的表达。因此，核因子-kappaB活性的失调被认为是各种癌症发生和发展的主要因素。我们最近已经证明，在MALT淋巴瘤中，两个独立的染色体易位针对不同的基因集，实际上影响相同的细胞内信号转导途径，并导致共同的生理效应，即戏剧性和无调控地诱导核因子-kappaB活性。这两种易位共同存在于大多数MALT淋巴瘤中，提示核因子-kappaB的诱导在本病的发病机制中起重要作用。这项提议的长期目标是进一步确定这两个重新出现的染色体易位所针对的基因的蛋白质产物。对于一个易位，t(11；14)，Bcl10基因的表达被不适当地增强。Bcl10与一种新的蛋白MALT1结合，并激活该蛋白中类似caspase的半胱氨酸蛋白酶结构域。第二个易位t(11；18)导致了一个新的融合蛋白API2-MALT1的产生。我们的工作证明，在这两种情况下，MALT1半胱氨酸蛋白酶结构域都被激活，这一事件导致了NF-kappaB的非调控诱导。除了研究这些蛋白激活核因子-kappaB的分子机制外，我们还将建立MALT淋巴瘤的小鼠模型，以研究核因子-kappaB活性在疾病发生发展中的作用。核因子-kappaB的抑制剂也将被探索为潜在的新的治疗工具。我们有三个具体的目标：(1)确定MALT1蛋白酶的靶点及其与NF-kappaB诱导的相关性；(2)确定最终控制MALT1活性的上游信号通路；(3)建立MALT淋巴瘤的遗传小鼠模型。这些目标将涉及广泛的技术，这将使调查员为指导独立研究计划的职业生涯做好准备。

The NF-kappaB transcription factor has recently emerged as a critical regulator of cell fate. In most cases, NF-kappaB stimulates expression of a set of genes which promote both cell survival and proliferation. Accordingly, dysregulated NF-kappaB activity has been identified as a major contributing factor in the pathogenesis and progression of various cancers. We have recently demonstrated that two independent chromosomal translocations in MALT lymphoma, which target distinct sets of genes, actually impact the same intracellular signal transduction pathway and lead to a common physiologic effect, a dramatic and unregulated induction of NF-kappaB activity. Together, these two translocations are present in the majority of MALT lymphomas, suggesting that the induction of NF-kappaB plays an important role in the pathogenesis of this disease. The long-term objectives of this proposal are to further characterize the protein products of the genes targeted by these two re-current chromosomal translocations. With one translocation, t(11;14), expression of the Bcl10 gene is inappropriately enhanced. Bcl10 binds to a novel protein, MALT1, and activates a caspase-like, cysteine protease domain within this protein. The second translocation, t(11;18), results in the creation of a novel fusion protein, API2-MALT1. Our work has demonstrated that in both cases, the MALT1 cysteine protease domain is activated, an event which leads to the unregulated induction of NF- kappaB. In addition to studying the molecular mechanisms whereby these proteins activate NF-kappaB, we will develop a mouse model for MALT lymphoma in order to study the contribution that NF-kappaB activity makes toward the development and progression of the disease. Inhibitors of NF-kappaB will also be explored as potential novel therapeutic tools. We have three Specific Aims: (1) Identify targets of the MALT1 protease and their relevance to NF-kappaB induction, (2) identify upstream signaling pathways which ultimately control MALT1 activity, and (3) Develop a genetic mouse model for MALT lymphoma. These aims will involve a wide range of techniques which will prepare the investigator for a career directing an independent research program.