AKT2 ONCOGENE AND HUMAN ONCOGENESIS

AKT1和AKT2是病毒癌基因v-AKT的人类同源物。我 先前证明了AKT1是v-的真正的人类对应物- AKT和AKT2编码一种新的相关蛋白质--丝氨酸-苏氨酸 激活剂。最近，AKT1被发现被多种生长因子激活 因子通过PI 3-激酶，而AKT2激酶的激活 仅针对PDGF进行检查。PDGF激活AKT2， 但显著低于AKT-1。 Akt2已经在相当数量的人类卵巢中被发现， 胰腺癌、肺癌和乳腺癌。我最近证明了这一点 AKT2过表达可转化NIH3T3细胞，而AKT1过表达 没有被证明是致癌的。此外，我还展示了 AKT2在有丝分裂和活跃分裂的细胞中上调。这些 数据提示，AKT2和AKT1的信号转导通路可能 不同的是，AKT2可能在人类恶性肿瘤中发挥重要作用。 因此，我建议阐明AKT2的正常细胞功能 从而更好地了解AKT2在人类肿瘤发生中的作用。首先，我会 检查一大系列乳腺癌、肺癌和胰腺癌以 确定AKT2改变的临床病理意义。 第二，使用细胞系的体外和体内肿瘤发生模型 和转基因小鼠，将被用来定义这一角色 AKT2在乳腺癌发生中的作用。第三，AKT2信号通路 将通过其活性和磷酸化来检测 酵母双杂交鉴定其相互作用蛋白 系统。最后，我对AKT2的综合和周转率进行了检验 在细胞周期的不同阶段，特别是G2和M期，以及 反义AKT2对肿瘤细胞的调控作用 乳腺和卵巢癌细胞的表型来概括我以前的 胰腺癌的临床观察。拟议的调查将 提供有关AKT2在细胞周期中的作用的非常重要的信息 控制和恶变以及可能的目标 癌症治疗。

AKT1 and AKT2 are human homologues of the viral oncogene v-akt.. I previously demonstrated that AKT1 is the true human counterpart of v- akt and that AKT2 encodes a novel related protein serine-threonine kinase. Recently, AKT1 was identified to be activated by various growth factors through PI 3-kinase; whereas AKT2 kinase activation has been examined only with respect to PDGF. The activation of AKT2 by PDGF, however, was significantly lower than that of AKT 1. Alterations of AKT2 have been identified in a significant numbers of human ovarian, pancreatic, lung, and breast carcinomas. I recently demonstrated that overexpression of AKT2 can transform NIH 3T3 cells, whereas AKT1 has not been shown to be oncogenic. In addition, I have also demonstrated that AKT2 is up-regulated in mitotic and actively dividing cells. These data suggest that the signal transduction pathways of AKT2 and AKT1 may differ and that AKT2 may play a significant role in human malignancy. Therefore, I propose to elucidate the normal cellular functions of AKT2 and thus to better understand AKT2 in human oncogenesis. First, I will examine a large series of breast, lung, and pancreatic carcinomas to determine the clinicopathological significance of AKT2 alterations. Second, in vitro and in vivo models of tumorigenesis, using cell lines and transgenic mice respectively, will be employed to define the role of AKT2 in breast cancer development. Third, the AKT2 signaling pathway will be examined through its activity and phosphorylation in addition to identification of its interacting proteins by yeast two-hybrid system. Finally, I Bill examine synthetic and turnover rates of AKT2 at different stages of the cell cycle, especially G2 and M phases, and also the ability of antisense AKT2 in modulation of the malignant phenotype in breast and ovarian cancer cells to generalize my previous observation in pancreatic cancer. The proposed investigations will provide very important information about the role of AKT2 in cell cycle control and malignant transformation as well as the possible target for cancer therapy.