AEG-1: Novel Gene Involved in Malignant Glioma

AEG-1：参与恶性胶质瘤的新基因

• 批准号: 7737398
• 负责人: PAUL B FISHER
• 金额: $ 31.02万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7737398
• 关键词: Adenoviruses; Affect; Animal Model; Animals; Antibodies; Apoptosis; Astrocytes; Binding; Biological; Brain; C-terminal; CREB-binding protein; Cell Nucleus; Cells; Co-Immunoprecipitations; Consensus; Coomassie blue; DNA Binding Domain; Development; Diffuse; Disease; Disease Progression; Doxycycline; Embryo; Endoplasmic Reticulum; Etiology; Evaluation; Excision; Fibroblasts; Future; Gene Expression; Gene Targeting; Generations; Genes; Genetic Transcription; Glial Fibrillary Acidic Protein; Glioma; HIV-1; Human; In Vitro; Indium; Inositol; Invaded; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Molecular; N-terminal; NF-Kappa B p65; NF-kappa B; NFKB Signaling Pathway; Normal Cell; Nuclear Protein; Nuclear Proteins; Nude Mice; Oligonucleotide Microarrays; Oncogenes; Oncogenic; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphotransferases; Play; Property; Proteins; Radiation therapy; Ras Signaling Pathway; Rattus; Recurrence; Regulation; Resistance; Role; Sampling; Serum; Signal Pathway; Small Interfering RNA; Staining method; Stains; Starvation; Testing; Tetanus Helper Peptide; Tetracyclines; Therapeutic; Tissues; Transcription Coactivator; Transcriptional Activation; Transgenic Animals; Transgenic Mice; Translating; Virulence; Xenograft Model; base; brain tissue; chemotherapy; effective therapy; fetal; gain of function; gene therapy; glioma cell line; human CREBBP protein; improved; in vivo; innovation; insight; knock-down; loss of function; melanocyte; migration; mouse model; mutant; novel; novel therapeutics; overexpression; p65; promoter; protein protein interaction; public health relevance; research study; tumor

DESCRIPTION (provided by applicant): Malignant glioma is the most fatal of all brain cancers. The tumor invades into the surrounding tissue thus limiting complete removal by surgical resection resulting in recurrence. Identifying molecules involved in glioma invasion is an important step to develop rationally targeted effective therapies. We have demonstrated that the expression of Astrocyte Elevated Gene-1 (AEG-1) is increased in malignant glioma and inhibition of AEG-1 significantly decreases invasion and migration properties of malignant glioma cells. AEG-1 exerts its function by activating the NF-kB signaling pathway. In the nucleus, AEG-1 interacts with the p65 subunit of NF-kB as well as with CBP, an activator of transcription that augments NF-kB transcriptional activity. Thus AEG-1 functions as a co-activator of transcription. AEG-1 does not contain any classical DNA-binding domain or transcription activation domain indicating that it exerts its effects predominantly by interaction with other proteins. Additionally, AEG-1 also protects normal astrocytes from serum starvation-induced apoptosis by activating the PI3K/Akt pathway. The long-term objective of the present proposal is to unravel the molecular mechanism of malignant glioma generation and progression so that the garnered information might be exploited to develop novel therapeutic strategies for the more effective management of malignant-diffuse glioma tumors. The immediate objectives of the present proposal are to authenticate the role of AEG-1 in in vivo regulation of glioma invasion by developing an astrocyte-specific AEG-1-overexpresing transgenic mouse, elucidate in detail the molecular mechanism of AEG-1 function, especially in the context of regulation of NF-kB and PI3K/Akt activity and identify critical AEG-1-downstream genes required for migration and invasion of malignant glioma cells. Our proposed studies are innovative because we aim at understanding the functions of a novel gene AEG-1 that plays an essential role in malignant glioma progression. Successful completion of the proposed studies will generate novel insights into malignant glioma pathogenesis with potential to translate into an effective therapy for this aggressive and frequently fatal cancer. PUBLIC HEALTH RELEVANCE: Invasion into surrounding normal brain tissue is an underlying cause for incomplete surgical removal of malignant glioma tumors resulting in recurrence and fatality. Astrocyte Elevated Gene-1 (AEG-1) is overexpressed in malignant glioma tumors and plays an essential role in regulating invasive properties of malignant glioma cells. The proposed studies aim at understanding the molecular mechanism of AEG-1 function, both in vitro and in vivo in transgenic mouse models, which will pave the way for the development of future novel therapies of malignant glioma based on targeted inhibition of AEG-1.

描述（由申请人提供）：恶性神经胶质瘤是所有脑癌中最致命的。肿瘤侵入周围组织，从而限制了手术切除的完全切除，导致复发。识别参与神经胶质瘤侵袭的分子是开发合理靶向有效疗法的重要一步。我们已经证明，恶性胶质瘤中星形胶质细胞升高基因1（AEG-1）的表达增加，抑制AEG-1可显着降低恶性胶质瘤细胞的侵袭和迁移特性。 AEG-1通过激活NF-kB信号通路发挥其功能。在细胞核中，AEG-1 与 NF-kB 的 p65 亚基以及 CBP 相互作用，CBP 是一种转录激活剂，可增强 NF-kB 转录活性。因此，AEG-1 充当转录的共激活因子。 AEG-1 不包含任何经典的 DNA 结合结构域或转录激活结构域，表明它主要通过与其他蛋白质相互作用来发挥其作用。此外，AEG-1 还通过激活 PI3K/Akt 途径保护正常星形胶质细胞免受血清饥饿诱导的细胞凋亡。本提案的长期目标是揭示恶性胶质瘤生成和进展的分子机制，以便利用所获得的信息来开发新的治疗策略，以更有效地管理恶性弥漫性胶质瘤。本提案的直接目标是通过开发星形胶质细胞特异性 AEG-1 过度表达转基因小鼠来验证 AEG-1 在体内调节神经胶质瘤侵袭中的作用，详细阐明 AEG-1 功能的分子机制，特别是在调节 NF-kB 和 PI3K/Akt 活性的背景下，并鉴定迁移和侵袭所需的关键 AEG-1 下游基因。 恶性胶质瘤细胞。我们提出的研究具有创新性，因为我们的目的是了解一种新基因 AEG-1 的功能，该基因在恶性胶质瘤进展中发挥重要作用。成功完成拟议的研究将为恶性胶质瘤发病机制提供新的见解，并有可能转化为针对这种侵袭性且常常致命的癌症的有效疗法。公共卫生相关性：侵入周围正常脑组织是恶性神经胶质瘤手术切除不彻底、导致复发和死亡的根本原因。星形胶质细胞升高基因 1 (AEG-1) 在恶性胶质瘤中过度表达，在调节恶性胶质瘤细胞的侵袭特性中发挥重要作用。拟议的研究旨在了解转基因小鼠模型中 AEG-1 体外和体内功能的分子机制，这将为未来开发基于 AEG-1 靶向抑制的恶性胶质瘤新疗法铺平道路。