Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling.
Astrocyte elevated gene-1 (AEG-1) displays oncogenic properties. Its expression is elevated in diverse neoplastic states and it cooperates with Ha-ras to promote cellular transformation. Overexpression of AEG-1 augments invasion and anchorage-independent growth of transformed cells, while AEG-1 siRNA inhibits Ha-ras-mediated colony formation, supporting a potential functional role in tumorigenesis. Additionally, oncogenic Ha-ras induces AEG-1 expression through the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. In the present study, we investigated whether AEG-1 could induce serum-independent cell growth, another property of oncogenes. Overexpression of AEG-1 inhibited serum starvation-induced apoptosis through activation of PI3K-Akt signaling, one of the effector pathways induced by activated Ras. AEG-1 also affected the phosphorylation state of Akt substrates that are implicated in apoptosis suppression, including glycogen synthase kinase 3beta, c-Myc, murine double minute 2, p53, p21/mda-6 and Bad. Additionally, AEG-1 blocked the activity of serum starvation-induced caspases. Taken together, these observations provide evidence that AEG-1 is an oncogene cooperating with Ha-ras as well as functioning as a downstream target gene of Ha-ras and may perform a central role in Ha-ras-mediated carcinogenesis. Activation of survival pathways may be one mechanism by which AEG-1 exerts its oncogenic properties.
Lee
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SG
Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032, USA.
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Emdad
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Sarkar
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Franke
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Fisher
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D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000502:physiology; D018390:Gene Targeting; D011905:Genes, ras / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D016601:RNA-Binding Proteins; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology
D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016601:RNA-Binding Proteins; D018631:ras Proteins; C483039:MTDH protein, human