Altered Apoptotic Responses in Chemically-Resistant Mammalian Cell Variants

96-30362 Wyche 程序性细胞死亡是动物发育的正常部分，由特定的基因产物主动控制，并且是在胚胎和成体的各种细胞中发生的事件。程序性细胞死亡或细胞凋亡可以通过化学和物理处理在各种培养的细胞类型中诱导。然而，对细胞凋亡的分子机制知之甚少。这部分是由于细胞凋亡的正调控因子和负调控因子尚不清楚，部分是由于细胞凋亡信号通路中缺乏合适的突变体。本发明的目的是：a）从人细胞系（HL-60）中分离化学抗性凋亡细胞变体，并将这些变体分类为互补组; B）鉴定与化学诱导的细胞凋亡的早期进展特异性相关的结构和生物化学上的连续细胞变化; d）表征导致蛋白酶活化的特定事件以及凋亡细胞及其变体中蛋白质和DNA靶位点的改变。这些研究应导致凋亡信号通路的建设，并深入了解凋亡调控基因产物之间的关系，并在凋亡信号通路中的特定事件。 程序性细胞死亡是动物发育的正常部分，由特定的基因产物主动控制，是胚胎和成体中各种细胞中发生的事件。程序性细胞死亡或细胞凋亡可以通过化学和物理处理在各种培养的细胞类型中诱导。然而，对细胞凋亡的分子机制知之甚少。 ***

96-30362 Wyche Programmed cell death is a normal part of animal development, is actively controlled by specific gene products, and is an event that occurs in various cells in the embryo and in adults. Programmed cell death, or apoptosis, can be induced in various cultured cell types by chemical and by physical treatment. Yet little is known about the molecular mechanism of apoptosis. This is partly caused by the fact that the positive and negative regulators of apoptosis are as yet unknown and partly to the lack of suitable mutants in the apoptotic signaling pathway. The objectives of this proposal are: a) isolation of chemically-resistant apoptosis cell variants from a human cell line (HL-60) and classification of the variants into complementation groups; b) identification of sequential cellular changes, structurally and biochemically, that are specifically associated with early progression of chemically-induced cell apoptosis; d) characterization of specific events leading to the activation of proteases as well as alterations in protein and DNA target sites in apoptotic cells and their variants. These studies should lead to the construction of the apoptotic signaling pathway and to insights into the relationship between apoptosis regulatory gene products and to specific events in the apoptotic signaling pathway. %%% Programmed cell death is a normal part of animal development, is actively controlled by specific gene products, and is an event that occurs in various cells in the embryo and in adults. Programmed cell death, or apoptosis, can be induced in various cultured cell types by chemical and by physical treatment. Yet little is known about the molecular mechanism of apoptosis. ***