AEG-1: Novel Gene Involved in Malignant Glioma

总结 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，从而限制了通过手术切除的完全去除，导致复发。识别 胶质瘤侵袭相关分子的研究是开发合理靶向 有效的治疗。我们已经证明星形胶质细胞升高基因-1的表达 在恶性胶质瘤中，AEG-1的表达增加，并且AEG-1的抑制显著降低 恶性胶质瘤细胞的侵袭和迁移特性。AEG-1发挥其功能， 激活NF-B信号通路。在细胞核中，AEG-1与p65亚基相互作用， NF-B以及CBP，一种转录激活剂，可增强NF-B的转录 活动因此，AEG-1起着转录共激活因子的作用。AEG-1不含任何 经典的DNA结合结构域或转录激活结构域，表明它发挥其 主要是通过与其他蛋白质的相互作用。此外，AEG-1还可保护 血清饥饿通过激活PI 3 K/Akt通路诱导正常星形胶质细胞凋亡。 本提案的长期目标是阐明 恶性胶质瘤的产生和发展，以便收集的信息可能是 开发新的治疗策略，以更有效地管理 恶性弥漫性神经胶质瘤。本建议的近期目标是 验证AEG-1在胶质瘤侵袭的体内调节中的作用， 星形胶质细胞特异性AEG-1-过表达转基因小鼠，详细阐明了分子生物学机制。 AEG-1功能的机制，特别是在NF-B和PI 3 K/Akt调节的背景下 活性，并确定关键AEG-1下游基因所需的迁移和入侵， 恶性胶质瘤细胞我们提出的研究是创新的，因为我们的目的是了解 一个在恶性胶质瘤中起重要作用的新基因AEG-1的功能 进展成功完成拟议的研究将产生新的见解， 恶性胶质瘤的发病机制，有可能转化为有效的治疗方法， 侵袭性和经常致命的癌症。

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.