BRAP是一个含有RING finger结构域的泛素连接酶，可与泛素形成硫酯键，表明它属于最新的RCR泛素连接酶或甚至是新的泛素连接酶家族。我们的研究表明，BRAP可调节基底样乳腺癌（BLBC）细胞系中IκBα（NF-κB的主要抑制剂）的持续性泛素化和降解。BLBC是一种无法治愈的乳腺癌。众所周知，NF-κB信号通路在BLBC中是持续性激活的，并且在BLBC的肿瘤进展和转移中起关键作用。然而，BLBC中NF-κB的持续性激活机制尚不清楚。我们的研究表明，BRAP可能是控制NF-κB持续性激活，肿瘤细胞增殖，迁移，侵袭和转移的关键因素之一。在本申请项目中，我们将研究BRAP作为一种新型IκBα泛素连接酶的机制。我们还将使用细胞系和小鼠模型研究BRAP在NF-κB的持续性激活，BLBC肿瘤细胞的增殖，迁移，侵袭和转移中的作用。

Protein ubiquitylation plays important roles in many aspects of biological activities. The specificity of ubiquitylation is mainly controlled by ubiquitin ligases which recognize ubiquitin substrates. Thus far, four families of ubiquitin ligases have been identified in human genome. The newest family of ubiquitin ligases, called RCR ubiquitin ligase, contains one RING finger domain and two active cysteines. BRAP is a RING finger-containing ubiquitin ligase. Recent study indicated that BRAP could form a thioester bone with ubiquitin, although it only contains a single RING finger domain, suggesting it belongs to RCR or even a new family of ubiquitin ligases. Our recent studies found that BRAP regulates constitutive ubiquitylation and proteolysis of IκBα, a major inhibitor of NF-κB, in cell lines of basal-like breast cancer (BLBC) which is the deadest breast cancer with no cure available. It is well-known that the NF-κB signaling pathway is constitutively activated in BLBC, and plays critical roles in tumor progression and metastasis of BLBC. However, the mechanism of constitutive activation of NF-κB in BLBC is still unclear. Our data suggested that BRAP might be one of the key factors in control of constitutive activation of NF-κB, tumor progression and metastasis of BLBC. In this proposal, we will investigate the mechanism of BRAP both as a ubiquitin ligase of IκBα and as a new type of ubiquitin ligase. We will also determine whether BRAP is important for constitutive activation of NF-κB, tumor progression and metastasis of BLBC using both cell lines and mouse model.