PI3K/PTEN/Akt signaling and the genesis of cancer

PI3K/PTEN/Akt 信号传导与癌症的发生

• 批准号: 8628748
• 负责人: Nissim Hay
• 金额: $ 37.97万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628748
• 关键词: Ablation; Address; Affect; Applications Grants; BRCA1 gene; Binding Sites; Cancer cell line; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Proliferation; Cell Survival; Cells; Contact Inhibition; DNA Damage; Dependence; Development; Funding; Genes; Genetic; Genetic Translation; Goals; Hexokinase 2; Human; In Vitro; Incidence; Insulin; Knockout Mice; Lung; Malignant Neoplasms; Mammary Neoplasms; Mediating; Modeling; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Neoplasms; Oncogene Proteins; Oncogenic; PTEN gene; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Predisposition; Process; Protein Isoforms; Role; Serine; Signal Transduction; Testing; Therapeutic Effect; Tissues; Transgenic Mice; Xenograft procedure; cancer cell; cancer therapy; in vivo; malignant breast neoplasm; mouse model; public health relevance; transcription factor; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The serine/theronine kinase Akt, perhaps the most frequently activated oncoprotein in human cancers, and whose activation often exerts chemoresistance, is an attractive target for cancer therapy. Our long-term goals are to understand why Akt is frequently activated in human cancers, and to elucidate the mechanisms by which Akt activation contributes to the genesis of cancer, a critical step toward enhancing such therapy. We are using genetic approaches to evaluate the feasibility and the physiological consequences of Akt ablation for cancer therapy. Over the years, we have been delineating the functions of Akt both at the cellular and organismal levels. By employing mouse knockouts of the Akt genes, we uncovered several mechanisms by which Akt activity contributes to cell survival, cell proliferation, and susceptibility to oncogenic transformation. We employed several mouse models to show that Akt1 ablation inhibits the development of neoplasia in these models. The current major objectives of this grant application, at the cellular level, include understanding the role of Akt in cell proliferation and tumorigenesis and its dependence on mTORC1. At the organismal level, we will employ conditional deletions of the Akt genes in the mouse to determine the therapeutic effect on cancer developed in these mice. We will verify and further understand the consequences of Akt1 deletion versus Akt2 deletion on cancer development, progression and metastasis. Finally, we will assess whether the conditional deletion of hexokinase 2, a downstream effector of Akt, could affect tumor development, and whether it could be targeted for cancer therapy.

描述（由申请人提供）：丝氨酸/赛氨酸激酶Akt可能是人类癌症中最常激活的癌蛋白，其激活通常会产生化疗耐药性，是癌症治疗的一个有吸引力的靶点。我们的长期目标是了解为什么Akt在人类癌症中经常被激活，并阐明Akt激活促进癌症发生的机制，这是加强此类治疗的关键一步。我们正在使用遗传方法来评估Akt消融用于癌症治疗的可行性和生理后果。多年来，我们一直在细胞和组织水平上描述Akt的功能。通过小鼠敲除Akt基因，我们揭示了Akt活性促进细胞存活、细胞增殖和致癌转化易感性的几种机制。我们使用了几种小鼠模型来证明Akt1消融抑制了这些模型中肿瘤的发展。在细胞水平上，本次资助申请的主要目标包括了解Akt在细胞增殖和肿瘤发生中的作用及其对mTORC1的依赖性。在机体水平上，我们将采用小鼠中Akt基因的条件缺失来确定对这些小鼠癌症的治疗效果。我们将验证并进一步了解Akt1缺失与Akt2缺失对癌症发生、进展和转移的影响。最后，我们将评估Akt的下游效应物己糖激酶2的条件缺失是否会影响肿瘤的发展，以及它是否可以作为癌症治疗的靶点。