INTRACELLULAR MEDIATORS OF TGF EFFECTS

TGF 效应的细胞内介质

• 批准号: 2668022
• 负责人: Kathleen M Mulder
• 金额: $ 22.07万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2668022
• 关键词: antisense nucleic acid; biological signal transduction; cell cycle; cell growth regulation; cyclin dependent kinase; cyclins; enzyme activity; enzyme inhibitors; gastrointestinal epithelium; gene expression; growth inhibitors; mitogen activated protein kinase; phosphorylation; tissue /cell culture; transforming growth factors

DESCRIPTION (Adapted from the applicant's abstract): TGFbeta-based therapeutics may potentially be successful against epithelial cancers, since this autocrine polypeptide regulator inhibits the proliferation of responsive carcinoma cells and elicits differentiation-like effects. However, the signaling pathway(s) leading to the growth inhibitory effect of TGFbeta have not been elucidated. The principal investigator's previous data provided the first direct evidence for rapid activation of cytoplasmic signaling components (Ras and the mitogen-activated protein kinse ERK1) by TGFbeta in association with growth inhibition. Additional data suggests that the effects of TGFbeta on cell cycle components may also play a role in the growth inhibitory response to TGFbeta. The principal investigator hypothesizes that TGFbeta activation of ERK1 is upstream from the effects of TGFbeta on nuclear cell cycle components in the TGFbeta signaling pathway. Accordingly, the principal investigator will examine whether the activation of ERK1 by TGFbeta kinetically precedes the effects of TGFbeta on complexes between cyclins and cyclin-dependent kinases (Cdk's) in the nucleus. It is further hypothesized that the cytoplasmic and nuclear components modulated by TGFbeta may be linked in a manner analogous to that demonstrated in yeast with regard to the growth inhibitory effects of mating pheromones. That is, the MapK cascade in yeast directly leads to phosphorylation and transcriptional activation of a Cdk inhibitor (FAR1). Thus the principal investigator plans to investigate whether TGFbeta regulation of mammalian Cdk inhibitor p27Kip1 kinetically follows TGFbeta activation of ERK1 in asynchronous cultures of epithelial cells.

描述（改编自申请人的摘要）：基于 TGFbeta 治疗方法可能会成功对抗上皮癌， 因为这种自分泌多肽调节剂抑制增殖 癌细胞反应并引发分化样效应。 然而，导致生长抑制的信号通路 TGFbeta 的作用尚未阐明。校长 研究者之前的数据提供了第一个直接证据 细胞质信号传导成分（Ras 和 有丝分裂原激活蛋白激酶 ERK1) 通过 TGFbeta 与 生长抑制。其他数据表明 TGFbeta 的作用 对细胞周期成分的影响也可能在生长抑制中发挥作用 对 TGFbeta 的反应。首席研究员假设 TGFbeta 对 ERK1 的激活是 TGFbeta 对 ERK1 的影响的上游。 TGFbeta 信号通路中的核细胞周期成分。 因此，主要研究者将检查是否 TGFbeta 对 ERK1 的激活在动力学上先于 TGFbeta 的作用 细胞周期蛋白和细胞周期蛋白依赖性激酶 (Cdk) 之间的复合物 核。进一步推测细胞质和细胞核 由TGFbeta调节的成分可以以类似于以下的方式连接 在酵母中证明了生长抑制作用 的交配信息素。也就是说，酵母中的MapK级联直接导致 Cdk 抑制剂的磷酸化和转录激活 （远1）。因此，首席研究员计划调查是否 TGFbeta 对哺乳动物 Cdk 抑制剂 p27Kip1 的动力学调节 上皮细胞异步培养物中 TGFbeta 激活 ERK1 细胞。