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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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
References
Altomare DA, Testa JR . (2005). Perturbations of the AKT signaling pathway in human cancer. Oncogene 24: 7455–7464.
Bader AG, Kang S, Zhao L, Vogt PK . (2005). Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer 5: 921–929.
Barkett M, Gilmore TD . (1999). Control of apoptosis by Rel/NF-κB transcription factors. Oncogene 18: 6910–6924.
Britt DE, Yang DF, Yang DQ, Flanagan D, Callanan H, Lim YP et al. (2004). Identification of a novel protein, LYRIC, localized to tight junctions of polarized epithelial cells. Exp Cell Res 300: 134–148.
Brown DM, Ruoslahti E . (2004). Metadherin, a cell surface protein in breast tumors that mediates lung metastasis. Cancer Cell 5: 365–374.
Chen C, Sytkowski AJ . (2001). Erythropoietin activates two distinct signaling pathways required for the initiation and the elongation of c-myc. J Biol Chem 276: 38518–38526.
Datta SR, Brunet A, Greenberg ME . (1999). Cellular survival: a play in three Akts. Genes Dev 13: 2905–2927.
Downward J . (2003). Targeting RAS signaling pathways in cancer therapy. Nat Rev Cancer 3: 11–22.
Downward J . (2004). PI3-kinase, Akt and cell survival. Semin Cell Dev Biol 15: 177–182.
Emdad L, Sarkar D, Su ZZ, Lee SG, Kang DC, Bruce JN et al. (2007). Astrocyte elevated gene-1: recent insights into a novel gene involved in tumor progression, metastasis and neurodegeneration. Pharmacol Ther 114: 155–170.
Emdad L, Sarkar D, Su ZZ, Randolph A, Boukerche H, Valerie K et al. (2006). Activation of the nuclear factor kappa B pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis. Cancer Res 66: 1509–1516.
Evan GI, Vousden KH . (2001). Proliferation, cell cycle and apoptosis in cancer. Nature 411: 342–348.
Fisher PB . (1984). Enhancement of viral transformation and expression of the transformed phenotype by tumor promoters. In: TJ Slaga (ed). Tumor Promotion and Cocarcinogenesis In Vitro, Mechanisms of Tumor Promotion. CRC Press: FL, pp 57–123.
Fisher PB, Babiss LE, Weinstein IB, Ginsberg HS . (1982). Analysis of type 5 adenovirus transformation with a cloned rat embryo cell line (CREF). Proc Natl Acad Sci USA 79: 3527–3531.
Franke TF, Cantley LC . (1997). Apoptosis a bad kinase makes good. Nature 390: 116–117.
Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C . (2003). PI3K/Akt and apoptosis: size matters. Oncogene 22: 8983–8998.
Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK et al. (1995). The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81: 727–736.
Gregory MA, Qi Y, Hann SR . (2003). Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. J Biol Chem 278: 51606–51612.
Hahn WC, Dessain SK, Brooks MW, King JE, Elenbaas B, Sabatini DM et al. (2002). Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Mol Cell Biol 22: 2111–2123.
Hanahan D, Weinberg RA . (2000). The hallmarks of cancer. Cell 100: 57–70.
Jiang H, Lin J, Su ZZ, Herlyn M, Kerbel RS, Weissman BE et al. (1995). The melanoma differentiation-associated gene mda-6, which encodes the cyclin-dependent kinase inhibitor p21, is differentially expressed during growth, differentiation and progression in human melanoma cells. Oncogene 10: 1855–1864.
Jiang H, Su ZZ, Lin JJ, Goldstein NI, Young CSH, Fisher PB . (1996). The melanoma differentiation associated gene mda-7 suppresses cancer cell growth. Proc Natl Acad Sci USA 93: 9160–9165.
Kane LP, Shapiro VS, Stokoe D, Weiss A . (1999). Induction of NF-κB by the Akt/PKB kinase. Curr Biol 9: 601–604.
Kang DC, Su ZZ, Sarkar D, Emdad L, Volsky DJ, Fisher PB . (2005). Cloning and characterization of HIV-1-inducible astrocyte elevate gene-1, AEG-1. Gene 353: 8–15.
Kumar S . (2007). Caspase function in programmed cell death. Cell Death Differ 14: 32–43.
Lauder A, Castellanos A, Weston K . (2001). c-Myb transcription is activated by protein kinase B (PKB) following interleukin 2 stimulation of T cells and is required for PKB-mediated protection from apoptosis. Mol Cell Biol 21: 5797–5805.
Lebedeva IV, Su ZZ, Emdad L, Kolomeyer A, Sarkar D, Kitada S et al. (2007). Targeting inhibition of K-ras enhances Ad.mda-7-induced growth suppression and apoptosis in mutant K-ras colorectal cancer cells. Oncogene 26: 733–744.
Lee SG, Su ZZ, Emdad L, Sarkar D, Fisher PB . (2006). Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc. Proc Natl Acad Sci USA 103: 17390–17395.
Li Y, Dowbenko D, Lasky LA . (2002). AKT/PKB phosphorylation of p21Cip/WAF1 enhances protein stability of p21Cip/WAF1 and promotes cell survival. J Biol Chem 277: 11352–11361.
Mayo LD, Donner DB . (2001). A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 98: 11598–11603.
Mulcahy LS, Smith MR, Stacey DW . (1985). Requirement for ras proto-oncogene function during serum-stimulated growth of NIH3T3 cells. Nature 313: 241–243.
Nicholson KM, Anderson NG . (2002). The protein kinase B/Akt signaling pathway in human malignancy. Cell Signal 14: 381–395.
Osaki M, Oshimura M, Ito H . (2004). PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis 9: 667–676.
Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB . (1999). NF-κB activation by tumor necrosis factor requires the Akt serine–threonine kinase. Nature 401: 82–85.
Rich JN, Guo C, McLendon RE, Bigner DD, Wang XF, Counter CM . (2001). A genetically tractable model of human glioma formation. Cancer Res 61: 3556–3560.
Rossig L, Jadidi AS, Urbich C, Badorff C, Zeiher AM, Dimmeler S . (2001). Akt-dependent phosphorylation of p21 (Cip1) regulates PCNA binding and proliferation of endothelial cells. Mol Cell Biol 21: 5644–5657.
Su ZZ, Chen Y, Kang DC, Chao W, Simm M, Volsky DJ et al. (2003). Customized rapid subtraction hybridization (RaSH) gene microarrays identify overlapping expression changes in human fetal astrocytes resulting from human immunodeficiency virus-1 infection or tumor necrosis factor-α treatment. Gene 306: 67–78.
Su ZZ, Kang DC, Chen Y, Pekarskaya O, Chao W, Volsky DJ et al. (2002). Identification and cloning of human astrocyte genes displaying elevated expression after infection with HIV-1 or exposure to HIV-1 envelope glycoprotein by rapid subtraction hybridization, RaSH. Oncogene 21: 3592–3602.
Sutherland HG, Lam YW, Briers S, Lamond AI, Bickmore WA . (2004). 3D3/lyric: a novel transmembrane protein of the endoplasmic reticulum and nuclear envelope, which is also present in the nucleolus. Exp Cell Res 294: 94–105.
Vogelstein B, Kinzler KW . (2004). Cancer genes and the pathways they control. Nat Med 10: 789–799.
White JA, Carter SG, Ozer HL, Boyd AL . (1992). Cooperative of SV40T antigen and ras in progressive stages of transformation of human fibroblasts. Exp Cell Res 203: 157–163.
Willis SN, Adams JM . (2005). Life in the balance: how BH3-only proteins induce apoptosis. Curr Opin Cell Biol 17: 617–625.
Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC . (2001a). Cytoplasmic localization of p21Cip/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells. Nat Cell Biol 3: 245–252.
Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC . (2001b). HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol 3: 973–982.
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1210713
Keywords
This article is cited by
-
Expression patterns of AEG-1 in the normal brain
Brain Structure and Function (2023)
-
Harnessing the immune system against cancer: current immunotherapy approaches and therapeutic targets
Molecular Biology Reports (2021)
-
Adenovirus-mediated anti-AEG-1 ScFv expression driven by stathmin promoter inhibits tumor growth in cervical cancer
Cancer Cell International (2020)
-
mPGES-1/PGE2 promotes the growth of T-ALL cells in vitro and in vivo by regulating the expression of MTDH via the EP3/cAMP/PKA/CREB pathway
Cell Death & Disease (2020)
-
Upregulation of neuronal astrocyte elevated gene-1 protects nigral dopaminergic neurons in vivo
Cell Death & Disease (2018)