Mitotic Regulation of Apoptosis in Leukemia

白血病细胞凋亡的有丝分裂调节

基本信息

批准号：
7758840
负责人：
DEBANANDA PATI
金额：
$ 20.68万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7758840
关键词：
Affinity Chromatography 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 Ensure Enzyme Activation Enzymes Event Family Gel Chromatography Gene Expression Hematologic Neoplasms Hematopoietic Hematopoietic Neoplasms Human Immunoprecipitation In Vitro Induction of Apoptosis Ion Exchange 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 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 treatment strategy yeast two hybrid system

项目摘要

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.

当前癌症生物学的大部分工作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，而人们对这些途径知之甚少。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凋亡将为识别治疗中的新靶点提供新的范例血液系统恶性肿瘤和其他癌症。我们建议有丝分裂分离和细胞凋亡在机制上是相关的，并且对姐妹染色单体凝聚力重要的蛋白质在调节正常的细胞凋亡过程。放松对这一联合过程的管制可能会导致形成和血液癌症的进展以及耐药性白血病和淋巴瘤的发展。 Cohesin Rad21，一种有丝分裂调节蛋白，可能在细胞间的界面中发挥重要作用增殖和凋亡。 Rad21 在染色体分离和 DMA 损伤修复中发挥作用细胞增殖，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 在细胞凋亡中的新作用。检验有丝分裂的中心假设分离和细胞凋亡是相互关联的过程，我们将重点关注粘连蛋白 Rad21 的特定作用在细胞凋亡中。我们的目标是 (a) 鉴定早期在细胞核中裂解 Rad21 的核蛋白酶。细胞凋亡诱导阶段并阐明其在 Rad21 介导的细胞凋亡中的作用，(b) 鉴定蛋白质与细胞凋亡途径中的 C 端 Rad21 相互作用，以及 (c) 确定通过哪些途径 C 端 Rad21 放大白血病细胞系中的凋亡信号并激活效应器半胱天冬酶。这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和它们在致癌过程中的作用。了解粘连蛋白裂解的细节以及后续步骤白血病细胞中的凋亡级联有望导致新靶点和策略的确定血液癌症的治疗。此外，还确定了 C- 终末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抵抗细胞凋亡，并将有助于设计治疗化疗耐药性白血病的新策略。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Separase loss of function cooperates with the loss of p53 in the initiation and progression of T- and B-cell lymphoma, leukemia and aneuploidy in mice.

分离酶功能丧失与 p53 丧失共同促进小鼠 T 细胞和 B 细胞淋巴瘤、白血病和非整倍体的发生和发展。

DOI：
发表时间：
2011
期刊：
影响因子：
3.7
作者：
Mukherjee, Malini;Ge, Gouqing;Zhang, Nenggang;Huang, Eryong;Nakamura, Lanelle V;Minor, Marissa;Fofanov, Viacheslav;Rao, Pullivarthi H;Herron, Alan;Pati, Debananda
通讯作者：
Pati, Debananda

Interaction of Sororin protein with polo-like kinase 1 mediates resolution of chromosomal arm cohesion.

Sororin 蛋白与 polo 样激酶 1 的相互作用介导染色体臂凝聚力的解析。

DOI：
发表时间：
2011-12-02
期刊：
影响因子：
0
作者：
Zhang, Nenggang;Panigrahi, Anil K;Mao, Qilong;Pati, Debananda
通讯作者：
Pati, Debananda

Calpain-1 cleaves Rad21 to promote sister chromatid separation.

Calpain-1 裂解 Rad21 以促进姐妹染色单体分离。

DOI：
发表时间：
2011-11
期刊：
影响因子：
5.3
作者：
Panigrahi, Anil K;Zhang, Nenggang;Mao, Qilong;Pati, Debananda
通讯作者：
Pati, Debananda

MMTV-Espl1 transgenic mice develop aneuploid, estrogen receptor alpha (ERα)-positive mammary adenocarcinomas.

MMTV-Espl1 转基因小鼠产生非整倍体、雌激素受体α (ERα) 阳性乳腺癌。

DOI：
发表时间：
2014-11-27
期刊：
影响因子：
8
作者：
Mukherjee, Malini;Ge, Gouqing;Zhang, Nenggang;Edwards, David G;Sumazin, Pavel;Sharan, Shyam K;Rao, Pulivarthi H;Medina, Daniel;Pati, Debananda
通讯作者：
Pati, Debananda

Sororin is a master regulator of sister chromatid cohesion and separation.

索罗林是姐妹染色单体凝聚和分离的主要调节者。