MEMBRANE-BOUND RAS P21 REGULATION BY GAP AND LIPIDS

描述(改编自申请人的摘要)：该项目的长期目标 该项目旨在发现保护正常细胞免受癌症侵袭的药物 化疗。癌基因ras存在于大约30%的 人类肿瘤：在正常细胞中发现了正常的非致癌ras。这 正常的ras(但不是致癌的ras)可以被胞浆中的 蛋白质间隙导致细胞分裂受到抑制。这种差异可以 被通过GAP-RAS作用的化合物利用来抑制 正常细胞的增殖，使它们免受抗肿瘤药物的影响 增殖疗法。 以前关于GAP-ras相互作用的大多数工作都利用了可溶性ras。 由于脂质似乎调节GAP-ras相互作用，因此这一点很重要。 使用更具生理性的膜结合形式的ras p21。在第一阶段 在这项SBIR赠款中，将为膜结合的非结合蛋白构建一种检测方法 致癌ras蛋白及其受GAP的调节(特异靶1)。这个 然后，结合膜的ras将被用来研究调控的效果。 脂类(特效目标2)。在第一阶段之后，作用于 抑制正常的ras功能将被识别，并在相关 细胞和动物模型。

DESCRIPTION (Adapted from applicant's abstract):The long-term goal of this project is to discover drugs that will protect normal cells from cancer chemotherapy. The oncogene ras is present in approximately 30 percent of human tumors: a normal non-oncogenic ras is found in normal cells. This normal ras (but not oncogenic ras) can be switched off by the cytosolic protein GAP resulting in inhibition of cell division. This difference can be exploited by compounds that act through GAP-ras to inhibit the proliferation of normal cells, sparing them from the effects of anti- proliferative therapy. Most previous work on GAP-ras interactions has utilized soluble ras. Since lipids appear to regulate the GAP-ras interaction, it is important to use the more physiological membrane-bound form of ras p21. In Phase I of this SBIR grant, an assay will be constructed for membrane-bound non- oncogenic ras protein and its regulation by GAP (Specific Aim 1). The membrane-bound ras will then be used to study the effects of regulatory lipids (Specific Aim 2). Subsequent to Phase I, compounds acting to inhibit normal ras function will be identified, and tested in relevant cell and animal models.