Mitotic Regulation of Apoptosis in Leukemia

目前癌症生物学的大部分工作都集中在研究细胞生长和 增殖或程序性细胞死亡(细胞凋亡)途径单独存在，而对 这两个重要过程的共同调节。了解两个单元共有的流程和控制 增殖和细胞凋亡将为发现新的治疗靶点提供一个新的范例。 恶性血液病和其他癌症。我们认为有丝分裂分离和分裂的过程 细胞凋亡是机械连接的，对姐妹染色单体凝聚力重要的蛋白质在 调节正常的细胞凋亡过程。放松对这一联合过程的管制可能导致形成和 血液病的进展与难治性白血病和淋巴瘤的发展。 粘附素Rad21，一种有丝分裂调节蛋白，可能在细胞间的相互作用中发挥重要作用 增殖和凋亡。Rad21在染色体分离和DNA损伤修复中的作用 细胞增殖，但一旦诱导细胞凋亡，就会促进细胞死亡。我们的实验室是两个实验室之一 最近发现了Rad21在细胞凋亡中的一个新的作用。来检验有丝分裂的中心假说 分离和凋亡是相互联系的过程，我们将重点介绍粘附素蛋白Rad21的具体作用 在细胞凋亡中。我们的目标是：(A)鉴定在早期裂解细胞核中的Rad21的核蛋白酶 细胞凋亡诱导阶段及其在Rad21介导的细胞凋亡中的作用；(B)鉴定蛋白质 与C-末端Rad21在凋亡途径中的相互作用，以及(C)确定通过什么途径 在白血病细胞系中，RAD21的C末端放大了凋亡信号，并激活了效应半胱氨酸酶。这个 提出的一系列研究将提供关于有丝分裂蛋白如何调控细胞凋亡和 它们在癌症发生中的作用。了解粘附素切割的细节以及 白血病细胞中的凋亡级联反应有望导致识别新的靶点和策略 血液病癌症的治疗。此外，对C-C-的作用机制的鉴定。 末端RAD21促进程序性细胞死亡将有助于解释为什么白血病细胞能够逃避和 抗细胞凋亡，并将有助于设计治疗化疗耐药白血病的新策略。

Much of the current effort in cancer biology is concentrated on studying either the cell growth and proliferation or the programmed cell death (apoptosis) pathways individually, and little is known about the coregulation of these two vital processes. Understanding processes and controls common to both cell proliferation and apoptosis would provide a new paradigm for identifying novel targets in the treatment of hematologic malignancies and other cancers. We propose that the processes of mitotic segregation and apoptosis are mechanistically linked and that proteins important for sister chromatid cohesion play a role in regulating normal apoptotic processes. Deregulation of this joint process can lead to formation and progression of hematologic cancers and development of therapy-resistant leukemia and lymphoma. Cohesin Rad21, a mitotic regulatory protein may play an important role in the interface between cell proliferation and apoptosis. Rad21 functions in chromosome segregation and DMAdamage repair during cell proliferation but promotes cell death once apoptosis is induced. Our lab is one of two laboratories that have recently identified a novel role for Rad21 in apoptosis. To test the central hypothesis that mitotic segregation and apoptosis are linked processes, we will focus on specific roles of the cohesin protein Rad21 in apoptosis. Our aims are (a) to identify the nuclear protease that cleaves Rad21 in the nucleus at the early stage of apoptosis induction and to elucidate its role in Rad21 -mediated apoptosis, (b) to identify proteins interacting with C-terminal Rad21 in the apoptotic pathway, and (c) to determine the pathways through which C-terminal Rad21 amplifies apoptotic signals and activates effector caspases in leukemia cell lines. The series of studies proposed will provide novel information about how mitotic proteins regulate apoptosis and their role in carcinogenesis. Understanding the details of cohesin cleavage and subsequent steps in the apoptotic cascade in leukemic cells is expected to lead to the identification of novel targets and strategies for the treatment of hematologic cancers. Furthermore, identification of the mechanism through which C- terminal Rad21 promotes programmed cell death will help explain why leukemic cells are able to evade and resist apoptosis and will aid the design of new strategies for treating chemotherapy-resistant leukemia.