CELL CYCLE SPECIFIC CONTROL OF CELLULAR DIFFERENTIATION

拟议的研究继续调查细胞的调节， 分化 重点是早期细胞生理反应 到终末分化的诱导剂。 潜在的监管作用 RB（视网膜母细胞瘤）基因的研究将集中在。 获得的将有望促进潜在的临床应用， 治疗造血肿瘤的分化诱导剂 疾病 白血病的化疗历来依赖于相对 毒性药物杀死肿瘤干细胞。 替代方案是使用 可能毒性较小的药物诱导终末分化， 白血病细胞，从而阻止其增殖活性， 潜在地恢复一些分化的细胞， 被剥夺了。 为了能够最佳地利用这一新的 治疗方式，有必要知道各种代理人如何发挥作用 在细胞和分子水平上影响终末分化 肿瘤细胞 我们将用人类白血病细胞系来研究这个 这在体外是有区别的 一个靶向调控基因， 在这方面研究较少的是肿瘤抑制基因，其中 RB是视网膜母细胞瘤基因的原型。 该基因的表达具有 在影响终末分化中具有明显的调节作用。 因此 对评估肿瘤反应和药物功效变得感兴趣， 确定RB在诱导的终末分化过程中如何调节， 这些因素如何影响其表达。 分子机制 涉及RB肿瘤抑制因子的分化诱导治疗 因此，将研究基因在分化中的作用。 工作 一种假说认为RB基因在影响 终末分化 我们的初步证据表明RB 在终末凋亡发生前表达下调， 分化 使用多种药物诱导终末 HL-60人早幼粒细胞白血病细胞诱导分化的研究 体外模型，RB基因在影响诱导终末细胞凋亡中的作用 分化将通过表征其调控来研究， 表达式，然后通过以下方式对该表达式进行实验性操作： 分子生物学技术，以确定对细胞的影响， 区分的能力。因为分化可以随意诱导 在这些细胞中，它们提供了一个强大的工具， 过程

The proposed studies continue to investigate the regulation of cell differentiation. The emphasis is on early cell physiological responses to inducers of terminal differentiation. The potential regulatory role of the RB (retinoblastoma) gene will be focused on. The insight so gained will hopefully promote the potential clinical use of differentiation inducing agents to treat hematopoietic neoplastic disease. Chemotherapy of leukemia has historically relied on relatively toxic agents to kill the tumor stem cells. An alternative is to use potentially less toxic agents to induce the terminal differentiation of leukemia cells, thereby arresting their proliferative activity and potentially restoring some of the differentiated cells that the patient is otherwise deprived of. To be able to optimally exploit this new treatment modality, it becomes necessary to know how various agents act at the cellular and molecular level to effect terminal differentiation of neoplastic cells. We will study this using a human leukemia cell line which differentiates in vitro. One target regulatory gene that has been little studied in this regard is the tumor suppressor genes, of which the RB retinoblastoma gene is the prototype. Expression of this gene has an apparent regulatory role in effecting terminal differentiation. Thus it becomes of interest to assessing tumor response and drug efficacy to determine how RB is regulated during induced terminal differentiation and how such agents affect its expression. Molecular mechanisms of differentiation induction therapy involving the RB tumor suppressor gene's role in differentiation will thus be studied. The working hypothesis is that the RB gene has a regulatory role in effecting terminal differentiation. Our preliminary evidence indicates that RB expression is down-regulated anteceding onset of terminal differentiation. Using a variety of agents to induce terminal differentiation of HL-60 human promyelocytic leukemia cells as an in vitro model, the role of the RB gene in effecting induced terminal differentiation will be studied by characterizing regulation of its expression and then experimentally manipulating that expression by molecular biological techniques to determine the consequences on cellular ability to differentiate. Because differentiation can be induced at will in these cells, they provide a powerful tool for investigating this process.