TGF-BETA MODULATED GENE EXPRESSION

TGF-β 调节基因表达

• 批准号: 3203673
• 负责人: EDWARD B LEOF
• 金额: $ 14.04万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3203673
• 关键词: antisense nucleic acid; antiserum; cell cycle; cell growth regulation; cell line; cell transformation; complementary DNA; gene expression; genetic library; genetic regulation; growth factor; immunoprecipitation; laboratory rabbit; neoplastic transformation; phenotype; protein biosynthesis; regulatory gene; transforming growth factors; western blottings

The experiments proposed in this application are designed to elucidate the mechanisms by which transforming growth factor beta1 (TGFbeta1) stimulates colony formation in soft agar. TGFbeta is unique in that regard since it is the only supplement when added to serum containing medium which consistently initiates and maintains soft agar colony growth. Since the ability of normal anchorage-dependent cultures to grow in an anchorage-independent manner is one of the best in correlates with tumorigenicity, the identification of specific regulatory genes might provide insights to the initial, and presumably rate limiting, events controlling neoplastic growth. It is our contention that expression of a unique program of genes, relative to that required for monolayer growth, is initiated by TGFbeta1 for soft agar growth; transformation might result from the constitutive or altered expression of these genes. Once these genes have been activated, the normal cellular machinery needed for cell division is operative. Moreover, inhibiting the expression of these genes may reestablish many aspects of normal growth control. We will test these hypotheses by 1) identifying unique cDNAs whose expression is specifically modulated during TGFbeta1-stimulated suspension growth; 2) determining whether a common set of genes are similarly expressed and required in various transformed cell lines; and 3) characterizing the cell cycle and growth factor regulated expression of specific proteins encoded by the clones isolated in the previous aims. These studies will not only increase our understanding of the events leading to tumorigenicity, but hopefully suggest new targets for therapeutic intervention.

本申请中提出的实验旨在阐明 转化生长因子β1(TGFbeta1)的机制 刺激软琼脂中的菌落形成。TGFBeta的独特之处在于 考虑到它是添加到含有以下物质的血清中的唯一补充剂 始终如一地启动并维持软琼脂菌落的培养基 成长。因为依赖锚地的正常培养物生长的能力 以一种独立于锚地的方式是与 致瘤性，识别特定的调控基因可能 提供对初始事件以及可能的速率限制事件的洞察 控制肿瘤生长。我们的论点是，一种 相对于单层生长所需的独特的基因程序， 是由TGFbeta1启动的软琼脂生长；转化可能 由于这些基因的结构性或改变表达而产生的。一次 这些基因已经被激活，正常的细胞机制需要 细胞分裂是可行的。此外，抑制这些基因的表达 基因可以重建正常生长控制的许多方面。我们会 通过以下方法验证这些假设：1)识别表达为 在TGFbeta1刺激的悬浮生长过程中特异调节；2) 确定一组共同的基因是否有相似的表达 在各种转化的细胞系中所需的；以及3)表征 细胞周期和生长因子调控特定蛋白的表达 由先前目标中分离的克隆编码。这些研究将 不仅增加了我们对导致 致瘤性，但有希望为治疗提供新的靶点 干预。