INTRACELLULAR MEDIATORS OF TGF EFFECTS

描述(改编自申请人的摘要)：基于TGFbeta 治疗技术可能会在治疗上皮癌方面取得成功， 由于这种自分泌多肽调节剂抑制了细胞的增殖 反应灵敏的癌细胞，并引起类似分化的效应。 然而，导致生长抑制的信号通路(S) 转化生长因子β的作用尚未阐明。校长 调查人员之前的数据提供了第一个直接证据 快速激活细胞质信号组件(RAS和 丝裂原活化蛋白激酶ERK1)与转化生长因子β的关系 生长抑制。更多数据表明，转化生长因子β的作用 对细胞周期成分也可能起到抑制生长的作用 对TGFbeta的反应。首席调查员假设 转化生长因子β激活ERK1是转化生长因子β的作用的上游。 转化生长因子β信号通路中的核细胞周期成分。 因此，首席调查员将审查是否 转化生长因子β激活ERK1的动力学先于转化生长因子β的作用 细胞周期蛋白与细胞周期蛋白依赖性蛋白激酶复合体的研究 原子核。进一步推测，细胞质和细胞核 由TGFbeta调制的组件可以以类似于 在酵母中表现出的生长抑制效应 交配信息素。也就是说，酵母中的MAPK级联直接导致 对CDK抑制剂的磷酸化和转录激活的影响 (FAR1)因此，首席调查员计划调查 转化生长因子β对哺乳动物CDK抑制剂p27Kip1的动力学调节 在上皮细胞异步化培养中跟踪ERK1的转化生长因子β激活 细胞。

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.