NF-kB Signaling & Molec Pathogenesis of MALT Lymphoma

NF-κ B转录因子最近已成为细胞命运的关键调节因子。在大多数情况下，NF-κ B刺激一组基因的表达，促进细胞存活和增殖。因此，失调的NF-κ B活性已被鉴定为各种癌症的发病机制和进展中的主要促成因素。我们最近已经证明，两个独立的染色体易位MALT淋巴瘤，其目标是不同的基因组，实际上影响相同的细胞内信号转导途径，并导致一个共同的生理效应，一个戏剧性的和不受管制的诱导NF-κ B活性。总之，这两种易位存在于大多数MALT淋巴瘤中，表明NF-κ B的诱导在这种疾病的发病机制中起重要作用。该提案的长期目标是进一步表征这两种再流染色体易位所靶向的基因的蛋白质产物。一个易位，t（11;14），Bcl 10基因的表达是不适当的增强。Bcl 10与一种新的蛋白质MALT 1结合，并激活该蛋白质内的半胱氨酸蛋白酶样半胱氨酸蛋白酶结构域。第二个易位，t（11;18），导致产生一种新的融合蛋白，API 2-MALT 1。我们的工作已经证明，在这两种情况下，MALT 1半胱氨酸蛋白酶结构域被激活，导致NF-κ B的不受调节的诱导。除了研究这些蛋白质激活NF-κ B的分子机制外，我们还将开发MALT淋巴瘤的小鼠模型，以研究NF-κ B活性对疾病发展和进展的贡献。NF-kappaB抑制剂也将作为潜在的新型治疗工具进行探索。我们有三个具体目标：（1）鉴定MALT 1蛋白酶的靶点及其与NF-κ B诱导的相关性，（2）鉴定最终控制MALT 1活性的上游信号通路，和（3）开发MALT淋巴瘤的遗传小鼠模型。这些目标将涉及广泛的技术，这将为研究人员的职业生涯指导一个独立的研究计划。

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.