AEG-1: Novel Gene Involved in Malignant Glioma

摘要 恶性胶质瘤是所有脑癌中最致命的。肿瘤向周围侵袭 组织因此限制了手术切除的完全切除，从而导致复发。识别 参与胶质瘤侵袭的分子是发展合理靶向的重要一步 有效的治疗方法。我们已经证明星形胶质细胞上调基因-1的表达 (AEG-1)在恶性胶质瘤中升高，对AEG-1的抑制作用显著降低 恶性胶质瘤细胞的侵袭和迁移特性。AEG-1通过以下途径发挥其作用 激活核因子-B信号通路。在细胞核中，AEG-1与P65亚基相互作用。 以及与转录激活剂CBP一起增强核因子-B的转录。 活动。因此，AEG-1作为转录的共激活因子发挥作用。AEG-1不包含任何 经典的DNA结合域或转录激活域表明它发挥了 主要通过与其他蛋白质的相互作用来发挥作用。此外，AEG-1还可以保护 血清饥饿通过激活PI3K/Akt通路诱导正常星形胶质细胞凋亡。 目前这项提议的长期目标是解开 恶性胶质瘤的发生和发展因此获得的信息可能是 开发新的治疗策略，以更有效地管理 恶性弥漫性胶质瘤肿瘤。本提案的近期目标是 AEG-1在脑胶质瘤侵袭调节中的作用 星形胶质细胞特异性AEG-1过表达转基因小鼠，详细阐明其分子 AEG-1功能的机制，特别是在调节核因子-βB和PI3K/Akt的背景下 活性，并确定关键的AEG-1下游基因的迁移和侵袭所需的 恶性胶质瘤细胞。我们提出的研究是创新的，因为我们的目标是理解 在恶性胶质瘤中起重要作用的新基因AEG-1的功能 进步。拟议研究的成功完成将产生新的见解 恶性胶质瘤的发病机制有可能转化为有效的治疗方法 侵袭性的、常常致命的癌症。

Summary 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-¿B signaling pathway. In the nucleus, AEG-1 interacts with the p65 subunit of NF-¿B as well as with CBP, an activator of transcription, that augments NF-¿B 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-¿B 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.