Role of Survivin in Blood Stem Cell Cycle and Apoptosis

生存素在血液干细胞周期和细胞凋亡中的作用

• 批准号: 7261923
• 负责人: Louis M Pelus
• 金额: $ 32.11万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261923
• 关键词: Adult; Apoptosis; Apoptosis Regulator; Area; Biochemical; Biological Preservation; Blood; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cell Death; Cell Line; Cell Proliferation; Cell Survival; Cell division; Cells; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; Cyclins; Development; Disease; Disruption; Dominant-Negative Mutation; Engraftment; Event; Family; Gene Deletion; Growth Factor; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Link; Maintenance; Malignant Neoplasms; Mediator of activation protein; Mitosis; Modeling; Molecular; Mus; Normal Cell; Oncogenes; Outcome; Pathway interactions; Production; Protein Overexpression; Proteins; RNA Splicing; Regulation; Retroviridae; Role; Signal Pathway; Stem cells; TP53 gene; Tissues; Toxic effect; Transplantation; Tumor Suppressor Genes; Tumor Suppressor Proteins; base; cdc Genes; design; inhibitor-of-apoptosis protein; inhibitor/antagonist; novel; novel therapeutics; retroviral transduction; stem; survivin; therapeutic target

DESCRIPTION (provided by applicant): The inhibitor of apoptosis protein Survivin is overexpressed in most cancers and hematologic malignancies and is an indicator of aggressive disease and poor outcome. Survivin is widely expressed during development but not in most adult tissues, making it an attractive therapeutic target. We were the first to demonstrate that Survivin is expressed and growth factor regulated in normal hematopoietic stem cells (HSC). New evidence from several areas now supports a critical role in preservation of cell viability and maintenance of normal mitosis. This leads to 2 hypotheses. First, Survivin is a normal regulator of HSC and Survivin targeted therapies may have hematologic toxicities. We will modulate Survivin expression in adult mouse HSC using retroviruses and quantitate its effects on hematopoiesis by competitive repopulation following transplantation and its role as a potential oncogene. Second, Survivin is a critical and multifaceted mediator of the cell death versus cell division decisions in HSC and understanding Survivin pathways will identify new therapeutic targets. We will investigate signaling pathways that regulate Survivin production and the molecular/biochemical relationships between Survivin and the intracellular regulators of apoptosis and cell cycle, i.e., cyclins, cyclin dependent kinases (cdks), cdk inhibitors (CDKIs), and the p53 family of tumor suppressors. We will investigate these interactions in normal primary HSC, in novel hematopoietic and nonhematopoietic cell line models, in which Survivin expression/disruption can be transiently or conditionally modulated, and in mice, in which genes for cell cycle and apoptosis related proteins have been deleted. Understanding the hematologic consequence of normal and abnormal Survivin expression and defining the molecular mechanisms of act of Survivin in regulating cell survival, cell cycle progression, and cell division in normal HSC will provide important information on normal cell survival and cell cycle regulation critical to the design of safe and efficacious Survivin-based therapies that target cell cycle and apoptosis.

描述(申请人提供)：凋亡抑制蛋白Survivin在大多数癌症和血液系统恶性肿瘤中过度表达，是侵袭性疾病和不良预后的指标。Survivin在发育过程中广泛表达，但在大多数成人组织中不表达，使其成为一个有吸引力的治疗靶点。我们是第一个证明Survivin在正常的造血干细胞(HSC)中表达并调节生长因子的。来自多个领域的新证据现在支持了在保存细胞活力和维持正常有丝分裂方面的关键作用。这就引出了两个假设。首先，Survivin是HSC的正常调节因子，Survivin靶向治疗可能有血液学毒性。我们将利用逆转录病毒调控Survivin在成年小鼠HSC中的表达，并通过移植后竞争性再繁殖来定量其对造血的影响及其作为潜在癌基因的作用。其次，Survivin是HSC中细胞死亡与细胞分裂决定的关键和多方面的中介，了解Survivin通路将确定新的治疗靶点。我们将研究调节Survivin产生的信号通路，以及Survivin与细胞内凋亡和细胞周期调节因子，即细胞周期蛋白、细胞周期蛋白依赖性蛋白激酶(CDK)、细胞周期蛋白依赖性蛋白激酶抑制因子(CDKI)和肿瘤抑制因子P53家族之间的分子/生化关系。我们将在正常的原代HSC中，在新的造血和非造血细胞系模型中，其中Survivin的表达/中断可以被瞬时或有条件地调节，以及在小鼠中，其中细胞周期和凋亡相关蛋白的基因已经被删除，我们将研究这些相互作用。了解Survivin正常和异常表达对血液学的影响，明确Survivin在正常HSC中调控细胞存活、细胞周期进展和细胞分裂的分子机制，将为设计安全有效的以Survivin为基础的针对细胞周期和细胞凋亡的治疗方法提供重要信息。

项目成果

Internal Tandem Duplication in FLT3 Attenuates Proliferation and Regulates Resistance to the FLT3 Inhibitor AC220 by Modulating p21Cdkn1a and Pbx1 in Hematopoietic Cells.

• DOI: 10.1371/journal.pone.0158290
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Abe M;Pelus LM;Singh P;Hirade T;Onishi C;Purevsuren J;Taketani T;Yamaguchi S;Fukuda S
• 通讯作者: Fukuda S