Mitotic Regulation of Apoptosis in Leukemia

描述(申请人提供)：目前癌症生物学的大部分工作集中在单独研究细胞生长和增殖或程序性细胞死亡(凋亡)途径，而对这两个重要过程的共同调节知之甚少。了解细胞增殖和凋亡的共同过程和控制，将为在血液系统恶性肿瘤和其他癌症的治疗中识别新的靶点提供新的范例。我们认为，有丝分裂分离和凋亡的过程是机械联系的，对姐妹染色单体凝聚力重要的蛋白质在调节正常的凋亡过程中发挥作用。这一联合过程的放松可能导致血液病癌症的形成和发展，以及耐药白血病和淋巴瘤的发展。粘附素Rad21是一种有丝分裂调节蛋白，可能在细胞增殖和凋亡的界面上发挥重要作用。Rad21在细胞增殖过程中参与染色体分离和DNA损伤修复，但一旦诱导细胞凋亡就会促进细胞死亡。我们的实验室是最近发现Rad21在细胞凋亡中扮演新角色的两个实验室之一。为了验证有丝分裂分离和凋亡是相互联系的过程这一中心假设，我们将重点研究粘附素蛋白Rad21在凋亡中的特定作用。我们的目标是(A)鉴定在细胞凋亡诱导的早期阶段裂解细胞核中的Rad21的核蛋白酶，并阐明其在Rad21介导的细胞凋亡中的作用；(B)鉴定在凋亡途径中与C-末端Rad21相互作用的蛋白质；(C)确定在白血病细胞系中，C-末端Rad21放大凋亡信号和激活效应半胱氨酸酶的途径。提出的一系列研究将为有丝分裂蛋白如何调控细胞凋亡及其在癌症发生中的作用提供新的信息。了解白血病细胞中粘附素裂解的细节和随后的凋亡级联步骤有望导致确定治疗血液病癌症的新靶点和策略。此外，识别RAD21 C末端促进细胞程序性死亡的机制将有助于解释为什么白血病细胞能够逃避和抵抗凋亡，并将有助于设计治疗化疗耐药白血病的新策略。

DESCRIPTION (provided by applicant): 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 DMA damage 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.