TUMOR PROMOTER MACROPHAGE DIFFERENTIATION AND APOPTOSIS

化学和辐射致癌是一个多阶段的过程。 肿瘤发生、促进和发展的过程。休伯曼博士 肿瘤启动子诱导组织单核细胞分化的假设 导致巨噬细胞池的不适当扩张，导致组织损伤和 炎症，从而促进所需的克隆性扩张 在肿瘤促进过程中启动细胞。他正在调查 肿瘤启动子诱导髓系前体细胞向巨噬细胞分化及其机制 导致这种分化的信号转导系统。他的实验 将利用差异显示技术来识别基因 在人髓系HL-60白血病细胞变异体中差异表达 对巨噬细胞分化敏感或抵抗。功能界别 已识别基因的作用将通过检查 反义核酸对HL-60细胞同源基因的抑制作用 在适当的抗性细胞变异体中过表达正义cdna。使用这个 通过这种方法，休伯曼博士已经分离出一种编码一种新的激酶的基因， 它是由肿瘤促进剂佛波酯12-肉豆蔻酸酯13-醋酸酯(PMA)诱导的 HL-60细胞，在耐药细胞中缺失，对PMA介导的HL-60至关重要 差异化。 休伯曼博士建议进行实验，以确定 该激酶在巨噬细胞的信号转导途径中 差异化。他建议建立该激酶与其他 分化的介体，表征了这一生物功能 并使用两种方法研究该激酶的靶点和效应器 基因表达和蛋白质接触策略。此外，休伯曼博士 提出旨在分离和表征更多介体的实验 巨噬细胞分化的表达筛选和基因 互补性方法。

Chemical- and radiation-induced carcinogenesis is a multistage process involving tumor initiation, promotion and progression. Dr. Huberman hypothesizes that tumor-promoter-induced differentiation of tissue monocytes results in an improper expansion of macrophage pools, causing tissue damage and inflammation and thereby contributing to the required clonal expansion of initiated cells during tumor promotion. He is investigating tumor-promoter-induced macrophage differentiation of myeloid precursors and the signal-transduction system that leads to this differentiation. His experiments will utilize the differential display technique to identify genes differentially expressed in human myeloid HL-60 leukemia cell variants that are either susceptible or resistant to macrophage differentiation. A functional role for the identified genes will be established by examining the effect of antisense-mediated inhibition of the cognate mRNA in HL-60 cells, as well as by over expressing sense cDNA in appropriate resistant cell variants. Using this approach, Dr. Huberman has already isolated a gene coding for a novel kinase, which is induced by the tumor promoter phorbol 12-myristate 13-acetate (PMA) in HL-60 cells, absent in resistant cells, and critical for PMA-mediated HL-60 differentiation. Dr. Huberman proposes experiments designed to determine the precise role of this kinase in the signal transduction pathway leading to macrophage differentiation. He proposes to establish the kinase's relationships to other mediators of differentiation, characterize the biological function of this kinase, and investigate the kinase's targets and effectors using both gene-expression and protein contact strategies. In addition, Dr. Huberman proposes experiments aimed at isolating and characterizing additional mediators of macrophage differentiation using an expression screen and genetic complementation approach.