Mitotic Regulation of Apoptosis in Leukemia

白血病细胞凋亡的有丝分裂调节

• 批准号: 7174296
• 负责人: DEBANANDA PATI
• 金额: $ 20.17万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174296
• 关键词: Affinity; Amino Acids; Anaphase; Apoptosis; Apoptotic; B-Lymphocytes; Biochemical; Biological Assay; C-terminal; CSPG6 gene; Cancer Biology; Caspase; Cell Cycle; Cell Death; Cell Line; Cell Nucleus; Cell Proliferation; Cell Therapy; Cell physiology; Cell-Free System; Chromosome Segregation; Cleaved cell; Complex; Cytoplasm; DNA biosynthesis; Data; Death Domain; Death Receptor 5; Development; Disease Resistance; Endopeptidases; Ensure; Enzyme Activation; Enzymes; Event; Family; Gel Chromatography; Gene Expression; Hematologic Neoplasms; Hematopoietic; Hematopoietic Neoplasms; Human; Immunoprecipitation; In Vitro; Induction of Apoptosis; Ion-Exchange Chromatography Procedure; Joints; Laboratories; Lead; Leukemic Cell; Link; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metaphase; Mitochondria; Mitosis; Mitotic; Mitotic Cell Cycle; Nuclear; Nuclear Protein; Nuclear Proteins; Numbers; Pathway interactions; Peptide Hydrolases; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Process; Proteins; Regulation; Research; Research Personnel; Resistance; Role; Series; Signal Transduction; Sister Chromatid; Site; Staging; Stimulus; System; T-Cell Leukemia; Techniques; Testing; Tetanus Helper Peptide; Tumor Necrosis Factor Receptor; Two-Hybrid System Techniques; Work; Yeasts; base; cancer cell; carcinogenesis; cell growth; chemotherapy; cohesin; cohesion; design; genetic regulatory protein; in vivo; leukemia; leukemia/lymphoma; link protein; novel; protein aminoacid sequence; protein protein interaction; receptor; repaired; response; segregation; separase; therapy resistant; yeast two hybrid system

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.

描述（由申请人提供）：当前癌症生物学领域的大部分工作集中于单独研究细胞生长和增殖或程序性细胞死亡（细胞凋亡）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识别血液恶性肿瘤和其他癌症治疗中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过程在机制上是相关的，并且对姐妹染色单体凝聚力重要的蛋白质在调节正常细胞凋亡过程中发挥作用。这一联合过程的失调可能导致血液癌症的形成和进展以及耐药性白血病和淋巴瘤的发展。 Cohesin Rad21 是一种有丝分裂调节蛋白，可能在细胞增殖和凋亡之间的界面中发挥重要作用。 Rad21 在细胞增殖过程中在染色体分离和 DMA 损伤修复中发挥作用，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 在细胞凋亡中的新作用的两个实验室之一。为了检验有丝分裂分离和细胞凋亡是相关过程的中心假设，我们将重点关注粘连蛋白 Rad21 在细胞凋亡中的特定作用。我们的目标是 (a) 鉴定在细胞凋亡诱导早期在细胞核中裂解 Rad21 的核蛋白酶，并阐明其在 Rad21 介导的细胞凋亡中的作用，(b) 鉴定在细胞凋亡途径中与 C 端 Rad21 相互作用的蛋白质，以及 (c) 确定 C 端 Rad21 放大细胞凋亡信号和激活效应半胱天冬酶的途径 在白血病细胞系中。提出的一系列研究将提供有关有丝分裂蛋白如何调节细胞凋亡及其在癌发生中的作用的新信息。了解白血病细胞中粘连蛋白裂解和细胞凋亡级联中的后续步骤的细节预计将有助于确定治疗血液癌症的新靶点和策略。此外，鉴定C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性白血病的新策略。