AKT2 FUNCTION AND ONCOGENIC ACTIVITY

描述：（改编自研究者摘要）申请人 先前报道的AKT 2癌基因的扩增/过表达， 10%-20%的人胰腺癌和卵巢癌，而 AKT 1基因在人类癌症中很少被发现。 他们有 证明AKT 2的过表达转化NIH 3 T3细胞， AKT 2反义RNA抑制人胰腺癌细胞的致瘤性 显示AKT 2扩增/过表达的癌细胞。 AKT 2编码 一种氨基末端含有普列克底物蛋白的丝氨酸-苏氨酸激酶 同源（PH）结构域是许多信号分子特征。 的作用 AKT 2在信号转导中的作用迄今尚未详细研究。 最近，申请人已经观察到AKT 2被表皮细胞激活， 表皮生长因子（EGF）通过与AKT 1不同的途径。 此外，委员会认为， 他们已经表明，AKT 2在靶组织中大量表达， 胰岛素，例如，棕色脂肪和肌肉，这表明AKT 2激酶可以 参与葡萄糖转运。 这一广泛而长期的目标 该项目旨在阐明AKT 2蛋白的正常细胞功能， 确定人类癌症中AKT 2基因扰动的重要性。 所提出的实验被设计为检验AKT 2是一种细胞因子的假设。 一种重要的信号介质，有助于控制细胞 增殖，并且AKT 2基因的异常表达有助于 某些人类上皮肿瘤的发展或进展。 的 具体目标有三个方面：1）直接测试是否过度表达 Akt 2在转基因小鼠中是致癌的。 Akt 2转基因小鼠将用于 确定单独的Akt 2过表达在体内是否是致瘤的 模型 为了确定Akt 2的异常表达是否在 多步骤肿瘤发生，致瘤性也将在子代中进行检查。 Akt 2转基因小鼠与携带其他致癌转基因的小鼠杂交。 2)描述AKT 2在EGF-和EGF-受体转导中的作用。 胰岛素介导的信号 为了阐明正常的细胞功能， AKT 2，它们将描绘特定的EGFR信号转导通路 促进AKT 2的活化，并确定AKT 2在 葡萄糖转运 3)定义AKT 2与两个 通过酵母相互作用鉴定的潜在重要信号伴侣 诱捕 为了确定这些的生理意义 相互作用，我们将测试这两个候选AKT 2相互作用是否可以 调节AKT 2的激酶和转化活性。 总体看 拟议的研究将产生有关机制的重要信息， AKT 2介导细胞信号并阐明AKT 2 改变有助于瘤形成。

DESCRIPTION: (adapted from the investigator's abstract) The applicants previously reported amplification/overexpression of the AKT2 oncogene in 10%-20% of human pancreatic and ovarian carcinomas, whereas alterations of the related gene, AKT1, are rarely observed in human cancer. They have demonstrated that overexpression of AKT2 transforms NIH 3T3 cells, and that AKT2 antisense RNA inhibits the tumorigenic phenotype of human pancreatic cancer cells exhibiting amplification/overexpression of AKT2. AKT2 encodes a serine-threonine kinase whose amino-terminus contains a pleckstrin homology (PH) domain characteristic of many signaling molecules. The role of AKT2 in signal transduction has not been explored in detail to date. Recently, the applicants have observed that AKT2 is activated by epidermal growth factor (EGF) through a pathway distinct from that of AKT1. Moreover, they have shown that AKT2 is abundantly expressed in tissues targeted by insulin, e.g., brown fat and muscle, suggesting that the AKT2 kinase could be involved in glucose transport. The broad, long-term objective of this project is to elucidate the normal cellular function of the AKT2 protein and determine the importance of perturbations of the AKT2 gene in human cancers. The proposed experiments are designed to test the hypothesis that AKT2 is an important signal mediator that contributes to the control of cell proliferation, and that aberrant expression of the AKT2 gene contributes to the development or progression of certain human epithelial tumors. The specific aims are threefold: 1) Directly test whether overexpression of Akt2 is oncogenic in transgenic mice. Akt2 transgenic mice will be used to ascertain if overexpression of Akt2 alone is tumorigenic in an in vivo model. To determine if aberrant expression of Akt2 could be important in multistep oncogenesis, tumorigenicity will also be examined in progeny of Akt2 transgenic mice crossed with mice harboring other oncogenic transgenes. 2) Delineate the role of AKT2 in the transduction of EGF- and insulin-mediated signals. To elucidate the normal cellular function of AKT2, they will delineate the specific EGFR signal transduction pathway contributing to the activation of AKT2 and determine the role of AKT2 in glucose transport. 3) Define the interaction between AKT2 and two potentially important signaling partners identified by yeast interaction trapping. To determine the physiological significance of these interactions, we will test whether these two candidate AKT2 interactors can regulate the kinase and transforming activities of AKT2. Overall, the proposed studies will yield important information concerning mechanisms by which AKT2 mediates cellular signals and elucidate mechanisms by which AKT2 alterations contribute to neoplasia.