Mitotic Regulation of Apoptosis in Leukemia

目前癌症生物学的大部分努力都集中在研究细胞生长和肿瘤细胞增殖。 细胞增殖或程序性细胞死亡（凋亡）途径，并且对细胞增殖和细胞凋亡知之甚少。 共同调节这两个重要的过程。了解两个单元共同的流程和控制 细胞增殖和凋亡的研究将为确定治疗肿瘤的新靶点提供新的范例。 血液恶性肿瘤和其他癌症。我们认为有丝分裂分离和 细胞凋亡是机械联系的，对姐妹染色单体凝聚重要的蛋白质在 调节正常的凋亡过程。放松对这一联合过程的管制可能导致形成和 血液系统癌症的进展以及耐药性白血病和淋巴瘤的发展。 Cohesin Rad 21是一种有丝分裂调节蛋白，可能在细胞间界面中起重要作用 增殖和凋亡。Rad 21在染色体分离和DNA损伤修复中的作用 细胞增殖，但一旦诱导凋亡则促进细胞死亡。我们的实验室是 最近发现了Rad 21在细胞凋亡中的新作用。为了验证有丝分裂 分离和凋亡是相互联系的过程，我们将重点关注的具体作用的cohesin蛋白Rad 21 细胞凋亡我们的目标是：（a）鉴定在细胞核中早期切割Rad 21的核蛋白酶， 凋亡诱导阶段，并阐明其在Rad 21介导的凋亡中的作用，（B）鉴定蛋白质 在凋亡途径中与C-末端Rad 21相互作用，和（c）确定通过其 在白血病细胞系中，C-末端Rad 21放大凋亡信号并激活效应器半胱天冬酶。的 提出的一系列研究将为有丝分裂蛋白如何调节细胞凋亡提供新的信息， 在致癌作用中的作用。理解粘附素切割的细节和随后的步骤， 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， 血液系统癌症的治疗此外，确定的机制，通过C- 末端Rad 21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， 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.