COBRE PROJ 7: CONTROL OF TUMOR GROWTH BY RAS-RELATED PROTEINS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 杰弗里·克拉克，少年派 具体目标1：RASSF家族RAS效应器在转化中的研究 RAS癌基因被认为在超过三分之一的人类癌症的发生中发挥了关键作用。RAS似乎通过激活多个异源效应蛋白来发挥作用，这些效应蛋白调节控制生长和发育的协同信号通路。实验上，过量的RAS激活会导致强烈的转化，而最具特性的RAS效应蛋白本身就是癌蛋白。然而，RAS的过度激活也会导致细胞生长停滞和凋亡。这表明，RAS蛋白可能会激活一组效应器，而不是促进转化，而是介导生长抑制。似乎有理由认为，这样的效应系统必须在转化过程中被颠覆，才能发展成肿瘤。 具体目标2：开发新型RAS作用小分子抑制剂 20多年来，RAS一直被确定为靶向抗癌治疗的首选候选药物，但到目前为止，开发特定的RAS抑制剂的尝试被证明无效。最著名的尝试涉及一系列法尼基转移酶抑制剂，它们实际上对H-RAS有效，但对家族中最重要的成员K-RAS无效。最近的工作表明，在人类系统中，最重要的RAS效应器是RalGDS组效应器。这与在小鼠系统中的结果形成了鲜明对比，这些结果表明RAF是关键的效应器。目前还没有RalGDS功能的抑制剂被描述。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Geoffrey Clark, PI Specific Aim 1: Investigation of the RASSF family of Ras effectors in transformation The Ras oncogene has been implicated as a key player in the development of more than a third of human cancers. Ras appears to function by activating multiple, heterologous effector proteins that regulate synergistic signaling pathways controlling growth and development. Experimentally, excess Ras activation leads to vigorous transformation and the best characterized Ras effector proteins are themselves oncoproteins. However, excessive activation of Ras can also cause cells to undergo growth arrest and apoptosis. This suggests that Ras proteins may activate a sub-set of effectors that, rather than promoting transformation, mediate growth inhibition. It would seem reasonable to suppose that such effector systems would have to be subverted during the transformation process to allow progression to tumorigenicity. Specific Aim 2: Development of novel small molecule inhibitors of Ras action Ras has been identified as a prime candidate for targeted anti-cancer therapy for more than two decades, but attempts to develop specific inhibitors of Ras have so far proved ineffective. The best known attempt involved a series of Farnesyl transferase inhibitors that actually do work well on H-Ras but are ineffective against the most important member of the family, K-Ras. Recent work has shown that the most important Ras effector for transformation in human systems is the RalGDS group of effectors. This contrasts with results in murine systems which have implicated Rafs as the key effectors. No inhibitors of RalGDS function have been described.