PHARMACOLOGIC AND MOLECULAR CONTROL OF C-JUN IN LEUKEMIA

C-JUN 对白血病的药理学和分子控制

• 批准号: 3460095
• 负责人: MATTHEW L SHERMAN
• 金额: $ 11.58万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3460095
• 关键词: DNA; cell differentiation; cell growth regulation; cellular oncology; disease /disorder model; fibroblasts; gene expression; genetic promoter element; genetic regulatory element; genetic transcription; laboratory mouse; monocyte; myelogenous leukemia; myeloid stem cell; neoplasm /cancer genetics; neoplastic cell; northern blottings; nucleic acid sequence; posttranscriptional RNA processing; protooncogene; tumor necrosis factor alpha

The early response proto-oncogene c-jun has been implicated in cell growth and differentiation. The c-jun-encoded product is structurally and functionally similar to a component of the transcription factor AP-1. Jun/AP-1 binds to DNA sequences that regulate transcription of genes responsive to phorbol esters and growth factors. Previous work has demonstrated that HL-60 promyelocytic leukemia cells differentiate into monocyte-like cells following exposure to pharmacologic agents including phorbol esters and tumor necrosis factor (TNF). This induction of monocytic differentiation is associated with changes in expression of a variety of genes. For example, in contrast to the down-regulation of c-- myc RNA levels, monocytic differentiation is associated with increases in c-sis, c-fos, and TNF transcripts. Furthermore, HL-60 cells induced along the monocytic lineage express both the macrophage-specific colony stimulating factor (M-CSF), and the M-CSF receptor (c-fms) genes. The 5' flanking promotor region of the c-myc, TNF and M-CSF genes contain several elements with sequence homology to a Jun/AP-1 site which may be involved in the regulation of gene transcription. Preliminary results demonstrate that expression of c-jun is increased through activation of protein kinase C by phorbol esters such as 12-0-tetradecanoylphorbol-1.3- acetate (TPA). Moreover, treatment of HL-60 cells with TNF is also associated with an increase in c-jun transcripts. These results thus provide the basis for exploring the transcriptional regulation of c-jun during monocytic differentiation of human myeloid leukemia cells. Furthermore, the molecular mechanisms involved in the posttranscriptional regulation of c-jun gene expression will be studied. The cis-regulatory DNA elements and trans-acting proteins that control c-jun expression in myeloid cells will be identified. Thus, it is hoped that these studies will provide certain insights into the regulation of early response gene expression and possibly lead to the design of novel approaches to overcome the block in the differentiation of leukemia cells.

早期响应原始癌基因C-Jun与细胞有关 生长与分化。 C-Jun编码的产品在结构上是 在功能上与转录因子AP-1的组件相似。 JUN/AP-1与调节基因转录的DNA序列结合 响应佛比尔酯和生长因子。 以前的工作有 证明HL-60临时细胞性白血病细胞分化为 暴露于包括 佛波酯和肿瘤坏死因子（TNF）。 这种归纳 单核细胞分化与A表达的变化有关 多种基因。 例如，与C-下调相反 MYC RNA水平，单核细胞分化与增加有关 C-SIS，C-FOS和TNF转录本。 此外，HL-60细胞诱导 沿单核细胞谱系表达巨噬细胞特异性菌落 刺激因子（M-CSF）和M-CSF受体（C-FMS）基因。 5' C-MYC，TNF和M-CSF基因的侧翼启动子区域包含 与JUN/AP-1站点具有序列同源性的几个元素可能是 参与基因转录的调节。 初步结果 证明C-Jun的表达通过激活而增加 佛比尔酯（例如12-0-四烷酰基-1.3-）的蛋白激酶C 醋酸盐（TPA）。 此外，用TNF处理HL-60细胞也是 与C-JUN转录本的增加有关。 因此，这些结果 提供探索C-Jun的转录调节的基础 在人髓样白血病细胞的单核细胞分化过程中。 此外，转录后涉及的分子机制 将研究C-Jun基因表达的调节。 顺式调节 DNA元素和反式作用蛋白控制C-JUN表达 将鉴定髓样细胞。 因此，希望这些研究 将为早期反应基因调节提供某些见解 表达并可能导致新颖方法的设计 克服白血病细胞分化的阻滞。