Dysregulation of ubiquitination in MALT lymphomas

描述（由申请方提供）：粘膜相关淋巴组织（MALT）淋巴瘤是最常见的淋巴瘤类型，发生于淋巴结组织。这些淋巴瘤几乎影响人体的每个器官，其中大多数发生在胃中。MALT淋巴瘤的发病机制与三种独立的染色体易位有关。两个经常性的易位分别导致Bcl 10和MALT 1的上调，Bcl 10是一种对抗原受体信号传导至NF-κ B至关重要的衔接蛋白，而MALT 1是一种推定的半胱氨酸蛋白酶。与MALT淋巴瘤相关的最常见的染色体易位产生细胞凋亡抑制因子2（C-IAP 2）和MALT 1之间的融合蛋白。我们已经发现C-IAP 2是Bcl 10的泛素连接酶，并且这种活性在cIAP 2-MALT 1融合中丢失，导致表达这种融合的MALT淋巴瘤中BcMO上调。BcMO表达在表达高水平MALT 1的MALT淋巴瘤中也上调，表明Bcl 10上调是MALT淋巴瘤的统一分子机制。我们计划进一步研究C-IAP 2和相关蛋白的功能和调节，以及它们控制的下游信号事件。这项工作不仅将揭示控制淋巴细胞增殖的信号转导，而且还将确定MALT淋巴瘤的分子机制，这可能会导致设计适当的治疗干预这种疾病。

DESCRIPTION (provided by applicant): Mucosa-associated lymphoid tissue (MALT) lymphoma is the most common type of lymphoma that arises in extranodal tissue. These lymphomas affect virtually every organ in the human body, with the majority of them occurring in the stomach. The pathogenesis of MALT lymphomas is associated with three independent chromosomal translocations. Two recurrent translocations lead to the up-regulation of Bcl10, an adapter protein critical for antigen receptor signaling to NF-kB, and MALT1, a putative cysteine protease, respectively. The most frequent chromosomal translocation associated with MALT lymphomas generates a fusion protein between cellular inhibitor of apoptosis 2 (C-IAP2) and MALT1. We have found that C-IAP2 is a ubiquitin ligase for Bcl10, and this activity is lost in the clAP2-MALT1 fusion, causing BcMO upregulation in MALT lymphomas expressing this fusion. BcMO expression is also up-regulated in the MALT lymphomas expressing high levels of MALT1, indicating that Bcl10 up-regulation is a unifying molecular mechanism of MALT lymphomas. We plan to further examine the function and regulation of C-IAP2 and related proteins as well as the downstream signaling events they control. This work will not only uncover the signal transduction governing lymphocyte proliferation but also determine the molecular mechanisms of MALT lymphomas, which may lead to the design of an appropriate therapeutic intervention for this disease.