Regulation of Cell Survival and Tumor Progression by Akt

Akt 对细胞存活和肿瘤进展的调节

基本信息

批准号：
7424938
负责人：
Vivek M Rangnekar
金额：
$ 24.69万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7424938
关键词：
Address Apoptosis Apoptotic BIRC4 gene Binding Biological Cell Nucleus Cell Proliferation Cell Survival Cell membrane Cell model Cell physiology Cells Clinical Cytoplasm Development Disease regression Epithelial Cells Event Future Gene Proteins Genetic Genetic Transcription Human Induction of Apoptosis Inhibition of Apoptosis Ionizing radiation LY294002 Lead Lesion Leucine Zippers Malignant Neoplasms Malignant neoplasm of prostate Molecular NF-kappa B Nuclear Nuclear Translocation Numbers PAWR gene PTEN gene Pathway interactions Phosphorylation Phosphorylation Site Play Principal Investigator Property Prostate Prostatic Neoplasms Protein Isoforms Proteins Reading Regulation Resistance Role Signal Pathway Signal Transduction Small Interfering RNA Specimen Tertiary Protein Structure Testing Therapeutic Tissues Tumor Suppressor Proteins angiogenesis base cancer cell cell motility cell type chemotherapeutic agent cytokine design glucose metabolism immortalized cell mouse model neoplastic cell novel prevent pro-apoptotic protein research study small hairpin RNA trafficking tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Akt is the focal point of a number of signaling pathways that regulate cell survival and tumor progression. Akt interacts with, and modifies via phosphorylation, many substrates involved in these cellular events. Owing to its anti-apoptotic properties, Akt plays a key role in promoting human cancer. Thus, the identification of molecules that interact with Akt may lead to a better understanding of the role of Akt in various local signaling networks and enable the development of strategies for specifically blocking signaling pathways involved in cancer development and progression. Par-4 is a leucine zipper domain protein that, when ectopically expressed, induces apoptosis in cancer cells but not in normal or immortalized cells. Apoptosis by ectopic Par-4 occurs by inhibition of NF-kappaB activity. As cancer cells contain reasonable levels of endogenous Par-4, we sought to determine whether Par-4 exists in an inactive form. Our Preliminary Studies reveal that Akt1 binds and inactivates endogenous Par-4, rendering it ineffective in apoptosis-induction. Moreover, inactivation of Akt1 releases Par-4 to induce apoptosis, implying that endogenous Par-4 is functionally active in the absence of Akt1. In view of the pro-survival functions of Akt1 and the pro-apoptotic functions of Par-4, the objective of this proposal is to study the molecular basis and functional relevance of the interaction between Akt1 and Par-4 in prostate cancer cell survival and tumor progression. Toward this end, we propose the following specific aims: Aim 1, elucidate the molecular basis for the isoform-specific effects of Akt on Par-4; Aim 2, determine the mechanism for cytoplasmic retention and inactivation of Par-4 by Akt1; and Aim 3, determine the downstream effects and functional relevance of Par-4 inhibition by Akt1 in tumor growth. Because PTEN loss is a well defined genetic lesion that elevates Akt activity and neutralizes the apoptotic pathway in the prostate, and contributes to prostate tumors in mouse models, this study will focus on the prostate cancer cell background to study the Akt1-Par-4 interaction. However, as the Akt1-Par-4 interaction occurs in diverse tumor cell types, we anticipate that the findings of this study will have broad implications in cancer. The findings will be further developed in future studies to design therapeutic strategies that can prevent Par-4 binding to Akt1 and induce apoptosis and tumor growth regression.

描述（由申请人提供）：Akt 是调节细胞存活和肿瘤进展的许多信号传导途径的焦点。 Akt 与参与这些细胞事件的许多底物相互作用并通过磷酸化对其进行修饰。由于其抗细胞凋亡特性，Akt 在促进人类癌症方面发挥着关键作用。因此，鉴定与 Akt 相互作用的分子可能有助于更好地了解 Akt 在各种局部信号网络中的作用，并能够制定特异性阻断癌症发生和进展中涉及的信号通路的策略。 Par-4 是一种亮氨酸拉链结构域蛋白，当异位表达时，会诱导癌细胞凋亡，但不会诱导正常或永生化细胞凋亡。异位 Par-4 导致的细胞凋亡是通过抑制 NF-kappaB 活性而发生的。由于癌细胞含有合理水平的内源性 Par-4，我们试图确定 Par-4 是否以非活性形式存在。我们的初步研究表明，Akt1 结合并灭活内源性 Par-4，使其在细胞凋亡诱导中无效。此外，Akt1 失活会释放 Par-4 来诱导细胞凋亡，这意味着内源性 Par-4 在 Akt1 缺失的情况下仍具有功能活性。鉴于Akt1的促生存功能和Par-4的促凋亡功能，本提案的目的是研究Akt1和Par-4之间相互作用在前列腺癌细胞存活和生存中的分子基础和功能相关性。肿瘤进展。为此，我们提出以下具体目标：目标1，阐明Akt对Par-4异构体特异性作用的分子基础；目标2，确定Akt1对Par-4的细胞质滞留和失活的机制；目标 3，确定 Akt1 抑制 Par-4 在肿瘤生长中的下游效应和功能相关性。由于 PTEN 缺失是一种明确的遗传损伤，可提高 Akt 活性并中和前列腺中的细胞凋亡途径，并导致小鼠模型中的前列腺肿瘤，因此本研究将重点关注前列腺癌细胞背景，以研究 Akt1-Par-4 相互作用。然而，由于 Akt1-Par-4 相互作用发生在不同的肿瘤细胞类型中，我们预计这项研究的结果将对癌症产生广泛的影响。这些发现将在未来的研究中得到进一步发展，以设计可以阻止 Par-4 与 Akt1 结合并诱导细胞凋亡和肿瘤生长消退的治疗策略。