Identifizierung und Charakterisierung von Proteinen, welche die Stabilität und Funktionalität des anti-apoptotische Bcl-2 Mitglieds A1/Bfl-1 regulieren

程序性细胞死亡（凋亡）的失调是允许细胞转化为癌细胞的难题之一。癌症中细胞凋亡失调的一种机制是抗细胞凋亡Bcl-2蛋白的过表达。A1/Bfl-1就是其中之一。我们已经发现，定义不明确的E3泛素连接酶HECTD 1直接与A1/Bfl-1相互作用并控制A1/Bfl-1的量。由于HECTD 1与已知的肿瘤抑制因子HACE 1相关，它可能调节细胞的存活和增殖，从而干扰恶性转化。我们提出了一个双重的方法来阐述HECTD 1的功能：在分子上，我们要定义的HECTD 1复合物的组成部分，和细胞，我们打算检查的效果HECTD 1缺陷B和T细胞在两个突变的动物模型。通过这种结合的方法，我们将提高我们对两种潜在危险蛋白质A1/Bfl-1和HECTD 1的基本理解，从而为最终干扰它们在癌症中的失调奠定基础。

Dysregulation of programmed cell death (apoptosis) is one piece of the puzzle allowing cells to trans-form into cancer cells. One mechanism of apoptosis dysregulation in cancer is overexpression of anti-apoptotic Bcl-2 proteins. A1/Bfl-1 is one of these proteins. We have found that the poorly defined E3 ubiquitin ligase, HECTD1, directly interacts with and controls the amount of A1/Bfl-1. As HECTD1 is related to the known tumor suppressor HACE1, it might regulate survival and proliferation of cells thereby interfering with malignant transformation. We propose a twofold approach to elaborate the function of HECTD1:molecularly, we want to define the components of the HECTD1 complex, and cellularly, we intend to examine the effect of HECTD1-deficiency on B and T cells in two mutant animal models. With this combined approach we will improve our basic understanding of two potentially hazardous proteins A1/Bfl-1 and HECTD1, thereby laying the groundwork toward eventually interfering with their dysregulation in cancer.