Lee Seok-Geun, Su Zao-Zhong, Emdad Luni, Sarkar Devanand, Fisher Paul B
Department of Urology, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17390-5. doi: 10.1073/pnas.0608386103. Epub 2006 Nov 6.
It is well established that Ha-ras and c-myc genes collaborate in promoting transformation, tumor progression, and metastasis. However, the precise mechanism underlying this cooperation remains unclear. In the present study, we document that astrocyte elevated gene-1 (AEG-1) is a downstream target molecule of Ha-ras and c-myc, mediating their tumor-promoting effects. AEG-1 expression is elevated in diverse neoplastic states, it cooperates with Ha-ras to promote transformation, and its overexpression augments invasion of transformed cells, demonstrating its functional involvement in Ha-ras-mediated tumorigenesis. We now document that AEG-1 expression is markedly induced by oncogenic Ha-ras, activating the phosphatidylinositol 3-kinase signaling pathway that augments binding of c-Myc to key E-box elements in the AEG-1 promoter, thereby regulating AEG-1 transcription. In addition, Ha-ras-mediated colony formation is inhibited by AEG-1 siRNA. This is a demonstration that Ha-ras activation of a tumor-promoting gene is regulated directly by c-Myc DNA binding via phosphatidylinositol 3-kinase signaling, thus revealing a previously uncharacterized mechanism of Ha-ras-mediated oncogenesis through AEG-1.
众所周知，Ha-ras基因和c-myc基因在促进细胞转化、肿瘤进展和转移方面存在协同作用。然而，这种协同作用背后的确切机制仍不清楚。在本研究中，我们证明星形胶质细胞上调基因-1（AEG-1）是Ha-ras基因和c-myc基因的下游靶分子，介导它们的促肿瘤作用。AEG-1在多种肿瘤状态下表达上调，它与Ha-ras协同促进细胞转化，其过表达增强转化细胞的侵袭能力，表明它在Ha-ras介导的肿瘤发生中发挥功能作用。我们现在证明致癌性Ha-ras能显著诱导AEG-1表达，激活磷脂酰肌醇3-激酶信号通路，该通路增强c-Myc与AEG-1启动子中关键E-box元件的结合，从而调节AEG-1转录。此外，AEG-1小干扰RNA可抑制Ha-ras介导的集落形成。这表明Ha-ras对促肿瘤基因的激活是通过磷脂酰肌醇3-激酶信号通路由c-Myc的DNA结合直接调控的，从而揭示了一种以前未被描述的Ha-ras通过AEG-1介导肿瘤发生的机制。
