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  • Original Article
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Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling

Abstract

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 3β, 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.

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Abbreviations

AEG-1:

astrocyte elevated gene-1

CREF:

cloned rat embryonic fibroblast

FBS:

fetal bovine serum

GSK3β:

glycogen synthase kinase 3β

HIV-1:

human immunodeficiency virus type 1

hTERT:

human telomerase reverse transcriptase

IKKα:

IκB kinase α

IM-PHFA:

immortalized PHFA

MDM2:

murine double minute 2

mTOR:

mammalian target of rapamycin

p21/mda-6:

p21 cyclin-dependent kinase inhibitor, which is melanoma differentiation associated gene-6

PHFA:

primary human fetal astrocyte

PI:

propidium iodide

PI3K:

phosphatidylinositol 3-kinase

PTEN:

phosphatase and tensin homolog

SV40:

simian virus 40

TNF-α:

tumor necrosis factor α

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Acknowledgements

We thank Dr David Volsky for providing primary human fetal astrocytes. This research was supported in part by National Institutes of Health Grant 5 P01 NS31492, the Goldhirsh Foundation, the Samuel Waxman Cancer Research Foundation (SWCRF) and the Chernow Endowment. PBF is the Michael and Stella Chernow Urological Center Research Scientist and a SWCRF Investigator.

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Correspondence to P B Fisher.

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Lee, SG., Su, ZZ., Emdad, L. et al. Astrocyte elevated gene-1 activates cell survival pathways through PI3K-Akt signaling. Oncogene 27, 1114–1121 (2008). https://doi.org/10.1038/sj.onc.1210713

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