Role of PI3 kinase/AKT2 signaling in ovarian oncogenesis

PI3激酶/AKT2信号在卵巢肿瘤发生中的作用

• 批准号: 6230163
• 负责人: Joseph R. Testa
• 金额: $ 5.55万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6230163
• 关键词: biological signal transduction; carcinoma; cell growth regulation; cell line; clinical research; enzyme activity; enzyme mechanism; female; gene expression; human subject; laboratory mouse; metastasis; neoplastic growth; oncogenes; ovary neoplasms; phosphatidylinositol 3 kinase; tissue /cell culture; women's health; yeast two hybrid system

DESCRIPTION: (Applicant's Description) AKT2 is a member of the Akt/protein kinase B family and is activated in response to phosphatidylinositol 3-kinase (PI 3-K)-mediated signals triggered at the cell membrane by growth factors. Amplification and/or overexpression of the AKT2 oncogene are associated with the development of human ovarian carcinomas. Therefore, understanding the role of AKT2 and PI 3-K-mediated signals in the growth regulation of human ovarian surface epithelial (HOSE) cells will contribute to a better understanding of the molecular mechanisms underlying ovarian oncogenesis, which is the broad, long-term objective of this project. The specific aims are: (1) Determine the involvement of AKT2, the related AKT1, and PI 3-K in human ovarian cancer. Examine the expression/kinase activity of AKT2, AKT1, and the catalytic subunit of PI 3-K (p110 alpha) in ovarian carcinoma specimens, and their expression in premalignant lesions in women predisposed to ovarian cancer. Correlate these laboratory findings with various clinicopathologic parameters to determine their clinical relevance. (2) Characterize the role of AKT2 in the regulation of physiological and neoplastic growth of HOSE cells in vitro. Evaluate the effect of the expression and/or activity of AKT2 on growth rate, cell cycle progression, and the induction of apoptosis. Using cDNA expression arrays, identify groups of genes associated with ovarian oncogenesis, whose expression is regulated in response to AKT2 expression/activity. (3) Determine the role of AKT2 in invasion and metastasis of HOSE cells and ovarian cancer cells. Using conditional retroviral expression constructs, investigate the potential involvement of AKT2 expression/activity in cell survival and the development of more invasive or metastatic phenotypes. (4) Identify modulators and substrates of AKT2. Using the yeast two-hybrid system and ovarian cancer-specific phage cDNA expression libraries, identify proteins that interact with AKT2 in the transduction of mitogenic signals in ovarian cancer cells, and determine the physiological significance of these interactions in HOSE cells. Overall, the studies proposed here will provide important new insights regarding the mechanisms by which AKT2 and PI 3-K-mediated signals contribute to ovarian oncogenesis, and may create potential avenues for therapeutic intervention.

描述：AKT2是Akt/蛋白激酶B家族的成员，在响应生长因子在细胞膜上触发的磷脂酰肌醇3-激酶（PI 3-K）介导的信号时被激活。AKT2癌基因的扩增和/或过表达与人类卵巢癌的发展有关。因此，了解AKT2和PI 3- k介导的信号在人卵巢表面上皮细胞（HOSE）生长调节中的作用，将有助于更好地了解卵巢肿瘤发生的分子机制，这是本项目广泛而长期的目标。具体目的是：(1)确定AKT2、相关的AKT1和PI 3-K在人卵巢癌中的作用。检测卵巢癌标本中AKT2、AKT1和pi3 - k催化亚基（p110 α）的表达/激酶活性，以及它们在卵巢癌易感女性癌前病变中的表达。将这些实验室结果与各种临床病理参数相关联，以确定其临床相关性。(2)表征AKT2在体外调控HOSE细胞生理和肿瘤生长中的作用。评估AKT2的表达和/或活性对生长速率、细胞周期进程和诱导凋亡的影响。利用cDNA表达阵列，鉴定与卵巢肿瘤发生相关的基因群，其表达受AKT2表达/活性的调控。(3)确定AKT2在HOSE细胞和卵巢癌细胞侵袭转移中的作用。使用条件逆转录病毒表达构建，研究AKT2表达/活性在细胞存活和更具侵袭性或转移性表型发展中的潜在参与。(4)鉴定AKT2的调制器和底物。利用酵母双杂交系统和卵巢癌特异性噬菌体cDNA表达文库，鉴定卵巢癌细胞中与AKT2相互作用的有丝分裂信号转导蛋白，并确定这些相互作用在HOSE细胞中的生理意义。总的来说，本文提出的研究将为AKT2和PI 3- k介导的信号促进卵巢肿瘤发生的机制提供重要的新见解，并可能为治疗干预创造潜在的途径。