AKT2 Function and Oncogenic Activity

描述：（由申请人提供）与其他AKT/蛋白激酶B家族相似 成员，AKT 2被生长因子通过磷脂酰肌醇激活 3-激酶（PI 3 K），从而介导参与多种细胞信号转导的信号。 过程如凋亡抑制、细胞增殖和胰岛素 信号AKT 2基因在AKT家族成员中是独特的，因为它 在胰岛素靶向的组织中优先表达， 在一些人胰腺癌和卵巢癌中扩增/过表达。在 此外，AKT 2激酶的激活似乎是常见的， 这些肿瘤类型。此外，AKT 2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。这个项目的广泛的长期目标是阐明 AKT 2的正常细胞功能，并确定AKT 2的意义 胰腺癌的发病率拟议的实验测试 假设AKT 2在正常发育中起重要作用， AKT 2的异常表达/激活有助于 一些胰腺癌的进展。具体目标有四个方面： 描述Akt 2基因敲除小鼠的表型以阐明Akt 2的功能 在正常的胚胎发育和成年组织中。除了有 表型/组织学表征，Akt 2（-/-）小鼠的代谢研究 将进行Akt 2和衍生细胞的研究，以确定Akt 2在胰岛素分泌中的作用。 新陈代谢.将检查促凋亡刺激的作用以确定 如果Akt 2的缺失降低了对程序性细胞死亡的抵抗力。2)确定 AKT 2表达/活性在人胰腺癌和胰腺癌中的机制作用 一种小鼠癌症模型。将在人类中评价AKT 2表达和活性。 胰腺肿瘤和早期病变。确定AKT 2的作用机制 胰腺癌中的活化、PTEN蛋白表达和P13 K活性 将被调查。为了阐明Akt 2在肿瘤发生中的机制作用， 将Akt 2（-/-）小鼠与PTEN（+/-）小鼠杂交以确定是否缺失PTEN（+/-）。 单独的Akt 2同种型能够减少与 PTEN缺失。3)确定IGF-1是否在胰腺癌中起重要作用 与AKT 2活化和AKT 2介导的细胞侵袭性有关 IGF-IR过度表达。此外，将采用胶原溶解测定法来测定 确定这一过程中涉及的机制。4)描述交互作用 AKT 2和一个新的适配器APPL之间的关系，在这个实验室克隆。的作用 APPL在细胞凋亡抑制和肿瘤发生中的作用将被阐明。总体看 拟议的研究将产生关于AKT 2功能的重要见解 和致癌机制。

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.