Role of Survivin in Blood Stem Cell Cycle and Apoptosis

描述（由申请人提供）：凋亡蛋白Survivin抑制剂在大多数癌症和血液恶性肿瘤中过表达，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在正常造血干细胞（HSC）中表达和生长因子受调节的研究。来自几个领域的新证据现在支持在保存细胞活力和维持正常有丝分裂中的关键作用。这就引出了两个假设。首先，Survivin是一种正常的HSC调节因子，Survivin靶向治疗可能具有血液学毒性。我们将使用逆转录病毒调节成年小鼠HSC中的Survivin表达，并量化其在移植后通过竞争性繁殖对造血的影响及其作为潜在致癌基因的作用。其次，在HSC中，Survivin是细胞死亡和细胞分裂决定的关键和多方面的介质，了解Survivin途径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、细胞周期蛋白依赖激酶（cdks）、cdk抑制剂（CDKIs）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、新型造血和非造血细胞系模型中研究这些相互作用，在这些模型中，Survivin的表达/破坏可以被短暂或有条件地调节，在小鼠中，细胞周期和凋亡相关蛋白的基因被删除。了解正常和异常Survivin表达的血液学后果，确定Survivin在正常HSC中调节细胞存活、细胞周期进展和细胞分裂的分子机制，将为正常细胞存活和细胞周期调节提供重要信息，这对于设计安全有效的以Survivin为基础的靶向细胞周期和细胞凋亡的疗法至关重要。

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.