CAMP AND RAS AND ENDOCRINE CELL PROLIFERATION

CAMP 和 RAS 与内分泌细胞增殖

• 批准号: 2144903
• 负责人: JUDY L MEINKOTH
• 金额: $ 14.18万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 1995-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2144903
• 关键词: DNA replication; G protein; antisense nucleic acid; biological signal transduction; blocking antibody; cell cycle; cell growth regulation; cyclic AMP; cyclic AMP receptors; gene expression; guanine nucleotide binding protein; hormone regulation /control mechanism; insulinlike growth factor; microinjections; mitogens; molecular cloning; mutant; protein kinase A; protooncogene; second messengers; thyrotropin; tissue /cell culture; transfection

The ability to respond to environmental signals is absolutely essential for proper development and cell survival. Extracellular signals in the form of growth factors affect many aspects of cell development including proliferation, differentiation and survival. The coordination of proliferation and differentiation affects not only embryonic development, but tissue replenishment and repair in the adult. The decision to divide or differentiate is influenced by numerous growth factors acting both individually and in concert to either stimulate or inhibit proliferation. One way in which growth factors act is through changes in gene expression. The elucidation of the molecular components of the pathways through which growth factors alter patterns of gene expression will provide potential targets for the augmentation or inhibition of these signalling pathways. The ability to manipulate these pathways has widespread applications in tissue maintenance and repair as well as in chemotherapeutic rationales. Moreover, the identification of the mediators of signal transduction pathways from the cell surface to the nucleus will provide a better understanding of the potential interactions between growth factors and insight into some of the cellular mechanisms of growth control. Much of our knowledge regarding signal transduction has resulted from the characterization of two predominant pathways active in fibroblasts, one including tyrosine kinase receptors and the other G-protein coupled receptors which activate phospholipases. Yet, elevations in cAMP are mitogenic in a variety of endocrine and other cell types. Moreover, activating mutations in the stimulatory G protein of adenylate cyclase have been isolated from a variety of tumors in which cAMP induces proliferation. We wish to elucidate the molecules which function in cAMP and ras mediated mitogenic pathways since activating mutations in both pathways have been found in human tumors. Thyroid follicular cells provide an ideal model system for this analysis since their growth can be stimulated by multiple signalling pathways including a cAMP mediated pathway stimulated by thyrotropin (TSH). Moreover, activating mutations in Gs and in all three cellular ras genes have been identified in thyroid adenomas, follicular and papillary carcinomas. Using needle microinjection and other molecular approaches, we will perform a molecular dissection of mitogenic pathways which include the ras protooncogene and cAMP as a second messenger. Microinjection allows for the introduction of putative signalling molecules or inhibitors directly into living cells in high concentrations. Unlike other techniques, biological effects in response to injected molecules can be measured in very short times. Since activating mutations in Gs and ras are found in a variety of human tumors, the identification of the molecular components of cAMP and ras mediated proliferation should contribute significantly to our understanding of growth control and transformation.

响应环境信号的能力绝对是必不可少的 为了适当发育和细胞存活。 细胞外信号 生长因素的形式影响细胞发育的许多方面，包括 增殖，分化和生存。 协调 扩散和分化不仅影响胚胎发育，而且会影响 但是成人的组织补充和修复。 划分的决定 或区分受众多作用的增长因素的影响 单独并协同刺激或抑制增殖。 生长因素通过基因变化而作用的一种方式 表达。 阐明途径的分子成分 通过其中，生长因子改变基因表达的模式将 为增强或抑制提供潜在的目标 信号通路。 操纵这些途径的能力 在组织维护和维修中广泛应用以及 化学治疗原理。 而且，识别 信号转导途径从细胞表面到介体 细胞核将更好地了解潜在相互作用 在生长因子和深入了解某些细胞机制之间 生长控制。 我们关于信号转导的许多知识是由 在成纤维细胞中活跃的两个主要途径的表征，一个 包括酪氨酸激酶受体和其他G蛋白耦合 激活磷脂酶的受体。 然而，营地的海拔是 各种内分泌和其他细胞类型的有丝分裂。而且， 腺苷酸环化酶刺激G蛋白中的激活突变 已经与营地诱导的多种肿瘤中分离出来 增殖。 我们希望阐明在CAMP和RAS中起作用的分子 介导的有丝分裂途径，因为在两种途径中激活突变 在人类肿瘤中发现。 甲状腺卵泡细胞提供 该分析的理想模型系统，因为可以刺激其增长 通过包括CAMP中介途径在内的多个信号通路 由甲状腺激素（TSH）刺激。 此外，激活GS中的突变 并且在所有三个细胞RAS基因中均已在甲状腺中鉴定 腺瘤，卵泡和乳头状癌。 使用针对针和其他分子方法，我们将 进行有丝分裂途径的分子解剖，其中包括 Ras Protooncogene和Camp作为第二使者。 微分注射允许 用于引入推定的信号分子或抑制剂 直接进入高浓度的活细胞。 与其他不同 技术，响应注射分子的生物学作用可以是 在很短的时间内测量。 由于激活GS和RAS中的突变 在各种人类肿瘤中发现 CAMP和RAS介导的增殖的分子成分应 为我们对增长控制的理解做出了重大贡献 转型。