Mitotic Regulation of Apoptosis in Leukemia

描述（由申请人提供）：目前癌症生物学的大部分工作都集中在单独研究细胞生长和增殖或细胞程序性死亡（凋亡）途径上，而对这两个重要过程的协同调节知之甚少。了解细胞增殖和凋亡的共同过程和控制将为确定血液恶性肿瘤和其他癌症治疗的新靶点提供新的范例。我们认为有丝分裂分离和细胞凋亡的过程是有机制联系的，对姐妹染色单体内聚起重要作用的蛋白质在调节正常的细胞凋亡过程中发挥作用。解除这一联合过程可导致血液学癌症的形成和进展以及治疗抵抗性白血病和淋巴瘤的发展。内聚蛋白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中起重要作用。Rad21在细胞增殖过程中参与染色体分离和DMA损伤修复，但一旦诱导细胞凋亡，则促进细胞死亡。我们的实验室是最近发现Rad21在细胞凋亡中的新作用的两个实验室之一。为了验证有丝分裂分离和细胞凋亡是相关过程的中心假设，我们将重点研究内聚蛋白Rad21在细胞凋亡中的具体作用。我们的目标是(a)鉴定在细胞凋亡诱导的早期阶段在细胞核中切割Rad21的核蛋白酶，并阐明其在Rad21介导的细胞凋亡中的作用，(b)鉴定凋亡途径中与c端Rad21相互作用的蛋白，以及(c)确定白血病细胞系中c端Rad21放大凋亡信号和激活效应半胱天冬酶的途径。提出的一系列研究将为有丝分裂蛋白如何调节细胞凋亡及其在癌变中的作用提供新的信息。了解白血病细胞凋亡级联中黏结蛋白切割的细节和随后的步骤有望导致血液肿瘤治疗的新靶点和策略的确定。此外，确定C末端Rad21促进程序性细胞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细胞凋亡，并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.