The role of Ras-related proteins in transformation

RAS癌基因是相关蛋白质大家族的一部分。其中许多RAS相关蛋白被怀疑在肿瘤转化中发挥作用。事实上，某些RAS相关蛋白似乎是RAS信号和转化的下游组成部分。 我们关注的是那些不仅与RAS在结构上有同源性，而且经历了与RAS相同类型的脂质加工的蛋白质，法尼化。旨在抑制法尼化的药物(法尼基转移酶抑制剂或FTI)是RAS功能所必需的，目前正在NIH进行临床试验。因此，了解其他法尼化蛋白在生长和发育中的整体重要性可能具有相当大的临床意义。 我们发现，新的RAS相关蛋白Rho6和Rho7也是法尼化的，似乎是RAS转化的某些方面的抑制剂。此外，这种抑制作用依赖于Rho6/7的法尼化。研究正在进行中，以确定这些蛋白质是否可能起到肿瘤抑制作用。如果是这样的话，长期使用FTI可能会无意中使肿瘤抑制因子失活。 我们还在研究一个新的RAS相关蛋白，我们通过数据库搜索确定了它，我们将其命名为ARHI2。该蛋白与RAS和肿瘤抑制基因Noey1/ARHI有同源性。

Ras oncogenes are part of a large family of related proteins. Many of these Ras-related proteins are suspected of playing a role in tumorigenic transformation. Indeed, certain Ras related proteins appear to serve as downstream components of Ras signaling and transformsation. We have focussed on those proteins which not only share structural homology to Ras, but also undergo the same type of lipid processing as Ras, farnesylation. Drugs directed at inhibiting farnesylation (Farnesyl transferase inhibitors or FTIs), which is essentail for Ras function, are currently in clinical trials at the NIH. Consequently, understanding the overall importance of other farnesylated proteins in growth and development may have considerable clinical relevance. We have found that the novel Ras-related proteins Rho6 and Rho7 are also farnesylated and appear to act as inhibitors of certain aspects of Ras transformation. Moreover, the inhibition is dependent upon Rho6/7 farnesylation. Studies are underway to determine if these proteins may play a role as tumor suppressors. If so, the long term use of FTIs may serve to inadvertantly inactivate tumor suppresors. We are also examining a novel Ras related protein identified by data base searching which we have designated ARHI2. This protein shares homology with Ras and with the tumor suppresor Noey1/Arhi.