Astrocyte Elevated Gene-1 (AEG-1) Is a Target Gene of Oncogenic Ha-ras Requiring Phosphatidylinositol 3-Kinase and c-Myc

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 46; pp. 17390 - 17395
• Main Authors: Lee, Seok-Geun, Su, Zao-Zhong, Emdad, Luni, Sarkar, Devanand, Fisher, Paul B.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14.11.2006; National Acad Sciences
• Subjects: Astrocytes; Base Sequence; Biological Sciences; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell growth; Cell lines; Cells, Cultured; Gene Expression; Genes; Humans; Membrane Proteins - genetics; Membrane Proteins - metabolism; Molecular Sequence Data; Oligonucleotide probes; Oligonucleotides; Oncology; Phosphatidylinositol 3-Kinases - metabolism; Plasmids; Promoter regions; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Signal Transduction; Small interfering RNA; Studies; Transcription factors; Transfection; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0608386103

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 tumorpromoting 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.