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.

目前，癌症生物学的许多努力都集中在研究细胞生长和扩散或编程细胞死亡（凋亡）途径单独，对此知之甚少这两个重要过程的核心构造。了解两个细胞共有的过程和控制增殖和凋亡将为识别新的目标提供新的范式血液学恶性肿瘤和其他癌症。我们建议有丝分裂分离的过程和细胞凋亡是机械上连接的，并且对于姐妹染色单体内聚力很重要的蛋白质在调节正常凋亡过程。消除这种联合过程可以导致形成，并且血液学癌症的进展和抗治疗性白血病和淋巴瘤的发展。粘蛋白RAD21，有丝分裂调节蛋白可能在细胞之间的界面中起重要作用增殖和凋亡。 RAD21在染色体分离和DMADAMAGE修复中起作用一旦诱导细胞凋亡，细胞增殖但会促进细胞死亡。我们的实验室是两个实验室之一最近已经确定了Rad21在凋亡中的新作用。测试有丝分裂的中心假设分离和凋亡是链接的过程，我们将重点介绍粘蛋白蛋白RAD21的特定作用在凋亡中。我们的目的是（a）识别早期将核中切割Rad21裂解的核蛋白酶凋亡诱导阶段并阐明其在Rad21介导的凋亡中的作用，（b）以鉴定蛋白质与凋亡途径中的C末端RAD21相互作用，（C）确定该途径 C末端RAD21放大了凋亡信号并激活白血病细胞系中的效应子胱天蛋白酶。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癌变中的作用。了解粘蛋白裂解的细节以及随后的步骤预计白血病细胞中的凋亡级联反应会导致鉴定新的目标和策略血液学癌的治疗。此外，识别c-的机制末端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凋亡，并将有助于设计用于治疗化学疗法性白血病的新策略。

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）

Higher-order orchestration of hematopoiesis: is cohesin a new player?

DOI：
10.1016/j.exphem.2012.09.010
发表时间：
2012-12
期刊：
EXPERIMENTAL HEMATOLOGY
影响因子：
2.6
作者：
Panigrahi, Anil K.;Pati, Debananda
通讯作者：
Pati, Debananda

Spatial quantitation of FISH signals in diploid versus aneuploid nuclei.

二倍体与非整倍体细胞核中 FISH 信号的空间定量。

DOI：
10.1002/cyto.a.22426
发表时间：
2014
期刊：
Cytometry. Part A : the journal of the International Society for Analytical Cytology
影响因子：
0
作者：
Shete,Amol;Rao,Pulivarthi;Pati,Debananda;Merchant,Fatima
通讯作者：
Merchant,Fatima

Handcuff for sisters: a new model for sister chromatid cohesion.

DOI：
10.4161/cc.8.3.7586
发表时间：
2009-02-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
0
作者：
Zhang N;Pati D
通讯作者：
Pati D

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.

DOI：
10.1371/journal.pone.0022167
发表时间：
2011
期刊：
PloS one
影响因子：
3.7
作者：
Mukherjee M;Ge G;Zhang N;Huang E;Nakamura LV;Minor M;Fofanov V;Rao PH;Herron A;Pati D
通讯作者：
Pati D

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