AKT2 Function and Oncogenic Activity

AKT2 功能和致癌活性

• 批准号: 6702622
• 负责人: Joseph R. Testa
• 金额: $ 46.21万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702622
• 关键词: apoptosis; enzyme activity; gene targeting; genetically modified animals; insulinlike growth factor; laboratory mouse; neoplasm /cancer invasiveness; pancreas neoplasms; phosphatidylinositol 3 kinase; protein kinase; protein protein interaction

DESCRIPTION: (provided by applicant) Like other AKT/protein kinase B family members, AKT2 is activated by growth factors through phosphatidylinositol 3-kinase (PI3K) and thereby mediates signals involved in diverse cellular processes such as apoptosis inhibition, cell proliferation, and insulin signaling. The AKT2 gene is unique among members of the AKT family, in that it is preferentially expressed in tissues targeted by insulin and is amplified/overexpressed in some human pancreatic and ovarian carcinomas. In addition, activation of the AKT2 kinase appears to be common occurrence in these tumor types. Moreover, AKT2 activation up-regulates IGF-I receptor expression and promotes invasiveness of pancreatic cancer cells in response to exogenous IGF-I. The broad, long-term objective of this project is to elucidate the normal cellular function of AKT2 and determine the significance of AKT2 perturbations in pancreatic cancer. The proposed experiments test the hypothesis that AKT2 plays an important role in normal development, and that aberrant expression/activation of AKT2 contributes to the development of progression of some pancreatic carcinomas. The specific aims are fourfold: 1) Delineate the phenotype of Akt2 knockout mice to elucidate the function of Akt2 in normal embryonic development and in adult tissues. In addition to the phenotypic/histologic characterization, metabolic studies of Akt2 (-/-) mice and derived cells will be carried out to determine the role of Akt2 in insulin metabolism. The effect of pro-apoptotic stimuli will be examined to determine if loss of Akt2 decreases resistance to programmed cell death. 2) Determine the mechanistic role of AKT2 expression/activity in human pancreatic cancer and in a mouse cancer model. AKT2 expression and activity will be evaluated in human pancreatic tumors and early lesions. To determine the mechanism(s) of AKT2 activation in pancreatic cancers, PTEN protein expression and P13K activity will be investigated. To elucidate the mechanistic role of Akt2 in oncogenesis, Akt2 (-/-) mice will be crossed with PTEN (+/-) mice to determine if loss of the Akt2 isoform alone is capable of diminishing oncogenesis associated with PTEN loss. 3) Determine if IGF-1 plays a significant role in pancreatic cancer cell invasiveness in connection with AKT2 activation and with AKT2-mediated IGF-IR overexpression. Furthermore, collagenolytic assays will be employed to define the mechanisms involved in this process. 4) Characterize the interaction between AKT2 and a novel adaptor APPL, cloned in this laboratory. The role of APPL in apoptosis inhibition and oncogenesis will be delineated. Overall, the proposed investigations will yield important insights regarding AKT2 function and oncogenic mechanisms.

描述：（由申请人提供）与其他 AKT/蛋白激酶 B 家族一样 成员们，AKT2 由生长因子通过磷脂酰肌醇激活 3-激酶（PI3K），从而介导参与多种细胞的信号 细胞凋亡抑制、细胞增殖和胰岛素等过程 发信号。 AKT2 基因在 AKT 家族成员中是独一无二的，因为它 优先在胰岛素靶向组织中表达，并且 在一些人类胰腺癌和卵巢癌中扩增/过表达。在 此外，AKT2 激酶的激活似乎在以下情况中很常见： 这些肿瘤类型。此外，AKT2 激活上调 IGF-I 受体 表达并促进胰腺癌细胞的侵袭性 外源性IGF-I。该项目的广泛、长期目标是阐明 AKT2 的正常细胞功能并确定 AKT2 的意义 胰腺癌的干扰。所提出的实验测试了 AKT2 在正常发育中发挥重要作用的假设 AKT2 的异常表达/激活有助于发展 一些胰腺癌的进展。具体目标有四个：1) 描绘 Akt2 敲除小鼠的表型以阐明 Akt2 的功能 在正常胚胎发育和成人组织中。除了 Akt2 (-/-) 小鼠的表型/组织学特征、代谢研究 并将进行衍生细胞测定Akt2在胰岛素中的作用 代谢。将检查促凋亡刺激的效果以确定 如果 Akt2 缺失会降低对程序性细胞死亡的抵抗力。 2）确定 AKT2 表达/活性在人类胰腺癌和胰腺癌中的机制作用 小鼠癌症模型。 AKT2 表达和活性将在人类中进行评估 胰腺肿瘤和早期病变。确定 AKT2 的机制 胰腺癌中的激活、PTEN 蛋白表达和 P13K 活性 将被调查。为了阐明 Akt2 在肿瘤发生中的机制作用， Akt2 (-/-) 小鼠将与 PTEN (+/-) 小鼠杂交，以确定是否丢失 Akt2 亚型单独能够减少与 PTEN 损失。 3) 确定IGF-1是否在胰腺癌中发挥重要作用 与 AKT2 激活和 AKT2 介导相关的细胞侵袭性 IGF-IR 过度表达。此外，胶原蛋白溶解测定将用于 定义此过程中涉及的机制。 4）描述交互的特征 AKT2 和本实验室克隆的新型适配器 APPL 之间的关系。的作用 APPL在细胞凋亡抑制和肿瘤发生中的作用将被阐述。总体而言， 拟议的研究将产生有关 AKT2 功能的重要见解 和致癌机制。