INTRACELLULAR MEDIATORS OF TGF EFFECTS

描述（改编自申请人摘要）：基于TGF β的 治疗可能成功地对抗上皮癌， 由于这种自分泌多肽调节剂抑制了 反应性癌细胞和elastomeric分化样效应。 然而，导致生长抑制的信号传导途径 TGF β作用尚未阐明。校长 研究人员先前的数据提供了第一个直接证据， 快速激活细胞质信号成分（Ras和 丝裂原活化蛋白激酶ERK1）通过TGF β与 生长抑制其他数据表明，TGF β的作用 对细胞周期成分的影响也可能在生长抑制中起作用 对TGF β的反应主要研究者假设， TGF β对ERK 1的激活作用位于TGF β对ERK的作用的上游。 TGF β信号通路中的核细胞周期组分。 因此，主要研究者将检查 TGF β激活ERK 1的动力学先于TGF β的作用 细胞周期蛋白和细胞周期蛋白依赖性激酶（Cdk's）之间的复合物 原子核进一步假设细胞质和细胞核 由TGF β调节的组分可能以类似于 这在酵母中证明了关于生长抑制作用， 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 （FAR1）。因此，首席研究员计划调查是否 哺乳动物Cdk抑制剂p27Kip1对TGF β的动力学调节 在上皮细胞非同步培养物中， 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.