Home LiteratureArticle Details
PMID: 17088530 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Astrocyte elevated gene-1 (AEG-1) is a target gene of oncogenic Ha-ras requiring phosphatidylinositol 3-kinase and c-Myc.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 46 ·2006-11-14 ·Pages 17390-5

Lee SG, Su ZZ, Emdad L, Sarkar D, Fisher PB

Abstract

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.

MeSH Terms
Base Sequence Cell Adhesion Molecules/genetics,metabolism Cells, Cultured Gene Expression Humans Membrane Proteins/genetics,metabolism Molecular Sequence Data Phosphatidylinositol 3-Kinases/metabolism Promoter Regions, Genetic/genetics Proto-Oncogene Proteins c-myc/genetics,metabolism Proto-Oncogene Proteins p21(ras)/genetics,metabolism RNA-Binding Proteins Signal Transduction
Chemicals
Cell Adhesion Molecules MTDH protein, human Membrane Proteins Proto-Oncogene Proteins c-myc RNA-Binding Proteins Proto-Oncogene Proteins p21(ras)
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Lee Seok-Geun
Department of Urology, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032, USA.
Su Zao-Zhong
Emdad Luni
Sarkar Devanand
Fisher Paul B
References (47)
47 references, click to expand
  1. Molecular basis for cell-specific regulation of the NADPH-cytochrome P450 oxidoreductase gene.
    Arch Biochem Biophys. 2000 Jul 1;379(1):97-108 PMID: 10864447
  2. Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway.
    J Biol Chem. 1996 Aug 23;271(34):20608-16 PMID: 8702807
  3. PEA3 sites within the progression elevated gene-3 (PEG-3) promoter and mitogen-activated protein kinase contribute to differential PEG-3 expression in Ha-ras and v-raf oncogene transformed rat embryo cells.
    Nucleic Acids Res. 2001 Apr 15;29(8):1661-71 PMID: 11292838
  4. A genetically tractable model of human glioma formation.
    Cancer Res. 2001 May 1;61(9):3556-60 PMID: 11325817
  5. Blocking oncogenic Ras signaling for cancer therapy.
    J Natl Cancer Inst. 2001 Jul 18;93(14):1062-74 PMID: 11459867
  6. Anticancer effect of retinoic acid via AP-1 activity repression is mediated by retinoic acid receptor alpha and beta in gastric cancer cells.
    Int J Biochem Cell Biol. 2002 Sep;34(9):1102-14 PMID: 12009305
  7. 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. 2002 May 16;21(22):3592-602 PMID: 12032861
  8. Ras family genes: an interesting link between cell cycle and cancer.
    J Cell Physiol. 2002 Aug;192(2):125-30 PMID: 12115718
  9. Targeting RAS signalling pathways in cancer therapy.
    Nat Rev Cancer. 2003 Jan;3(1):11-22 PMID: 12509763
  10. Insights into glutamate transport regulation in human astrocytes: cloning of the promoter for excitatory amino acid transporter 2 (EAAT2).
    Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1955-60 PMID: 12578975
  11. Unexpected induction of the human connexin 43 promoter by the ras signaling pathway is mediated by a novel putative promoter sequence.
    Mol Pharmacol. 2003 Apr;63(4):821-31 PMID: 12644583
  12. Transcriptional regulation of osteopontin and the metastatic phenotype: evidence for a Ras-activated enhancer in the human OPN promoter.
    Clin Exp Metastasis. 2003;20(1):77-84 PMID: 12650610
  13. Restoring apoptosis as a strategy for cancer gene therapy: focus on p53 and mda-7.
    Semin Cancer Biol. 2003 Apr;13(2):169-78 PMID: 12654260
  14. 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-alpha treatment.
    Gene. 2003 Mar 13;306:67-78 PMID: 12657468
  15. PTEN: from pathology to biology.
    Trends Cell Biol. 2003 Sep;13(9):478-83 PMID: 12946627
  16. Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization.
    J Biol Chem. 2003 Dec 19;278(51):51606-12 PMID: 14563837
  17. Transcriptional regulation of human excitatory amino acid transporter 1 (EAAT1): cloning of the EAAT1 promoter and characterization of its basal and inducible activity in human astrocytes.
    J Neurochem. 2003 Dec;87(6):1485-98 PMID: 14713304
  18. 3D3/lyric: a novel transmembrane protein of the endoplasmic reticulum and nuclear envelope, which is also present in the nucleolus.
    Exp Cell Res. 2004 Mar 10;294(1):94-105 PMID: 14980505
  19. Metadherin, a cell surface protein in breast tumors that mediates lung metastasis.
    Cancer Cell. 2004 Apr;5(4):365-74 PMID: 15093543
  20. The Ku protein complex interacts with YY1, is up-regulated in human heart failure, and represses alpha myosin heavy-chain gene expression.
    Mol Cell Biol. 2004 Oct;24(19):8705-15 PMID: 15367688
  21. Identification of a novel protein, LYRIC, localized to tight junctions of polarized epithelial cells.
    Exp Cell Res. 2004 Oct 15;300(1):134-48 PMID: 15383321
  22. ras oncogenes in human cancer: a review.
    Cancer Res. 1989 Sep 1;49(17):4682-9 PMID: 2547513
  23. Retinoic acid is a negative regulator of AP-1-responsive genes.
    Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6092-6 PMID: 1648728
  24. Identification of the promoter region of human interleukin 1 type I receptor gene: multiple initiation sites, high G+C content, and constitutive expression.
    Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2295-9 PMID: 8460136
  25. c-Myc cooperates with activated Ras to induce the cdc2 promoter.
    Mol Cell Biol. 1994 Sep;14(9):5710-8 PMID: 8065306
  26. Rac and Cdc42 induce actin polymerization and G1 cell cycle progression independently of p65PAK and the JNK/SAPK MAP kinase cascade.
    Cell. 1996 Nov 1;87(3):519-29 PMID: 8898204
  27. Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB.
    Nature. 1997 Feb 6;385(6616):544-8 PMID: 9020362
  28. Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein.
    Nature. 1997 Mar 13;386(6621):177-81 PMID: 9062190
  29. Transcriptional activation of the matrix metalloproteinase-9 gene in an H-ras and v-myc transformed rat embryo cell line.
    Oncogene. 1997 Apr 24;14(16):1995-8 PMID: 9150367
  30. Myc and Ras collaborate in inducing accumulation of active cyclin E/Cdk2 and E2F.
    Nature. 1997 May 22;387(6631):422-6 PMID: 9163430
  31. Cooperativity between oxidants and tumor necrosis factor in the activation of nuclear factor (NF)-kappaB: requirement of Ras/mitogen-activated protein kinases in the activation of NF-kappaB by oxidants.
    Am J Respir Cell Mol Biol. 1999 May;20(5):942-52 PMID: 10226064
  32. Coordinate regulation of basal and cyclic 5'-adenosine monophosphate (cAMP)-activated expression of human chorionic gonadotropin-alpha by Ets-2 and cAMP-responsive element binding protein.
    Mol Endocrinol. 2005 Apr;19(4):1049-66 PMID: 15637148
  33. NF-kappaB mediated IL-6 production by renal epithelial cells is regulated by c-jun NH2-terminal kinase.
    J Am Soc Nephrol. 2005 Jun;16(6):1603-11 PMID: 15843470
  34. Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1.
    Gene. 2005 Jun 20;353(1):8-15 PMID: 15927426
  35. Transformation of human and murine fibroblasts without viral oncoproteins.
    Mol Cell Biol. 2005 Aug;25(15):6464-74 PMID: 16024784
  36. Defining the domains of human polynucleotide phosphorylase (hPNPaseOLD-35) mediating cellular senescence.
    Mol Cell Biol. 2005 Aug;25(16):7333-43 PMID: 16055741
  37. Is mda-7/IL-24 a "magic bullet" for cancer?
    Cancer Res. 2005 Nov 15;65(22):10128-38 PMID: 16287994
  38. Oncogenic PI3K deregulates transcription and translation.
    Nat Rev Cancer. 2005 Dec;5(12):921-9 PMID: 16341083
  39. CCAAT/enhancer binding protein activation by PD98059 contributes to the inhibition of AhR-mediated 3-methylcholanthrene induction of CYP1A1.
    Xenobiotica. 2005 Oct-Nov;35(10-11):975-87 PMID: 16393856
  40. Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis.
    Cancer Res. 2006 Feb 1;66(3):1509-16 PMID: 16452207
  41. Transcription factor YY1: structure, function, and therapeutic implications in cancer biology.
    Oncogene. 2006 Feb 23;25(8):1125-42 PMID: 16314846
  42. Multiple Ras functions can contribute to mammalian cell transformation.
    Cell. 1995 Feb 24;80(4):533-41 PMID: 7867061
  43. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway.
    Cell. 1995 Jun 30;81(7):1137-46 PMID: 7600581
  44. Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs.
    Cell. 1995 Jun 30;81(7):1147-57 PMID: 7600582
  45. The MAPK signaling cascade.
    FASEB J. 1995 Jun;9(9):726-35 PMID: 7601337
  46. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis.
    Science. 1995 Nov 24;270(5240):1326-31 PMID: 7481820
  47. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability.
    Genes Dev. 2000 Oct 1;14(19):2501-14 PMID: 11018017
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0608386103
Published
2006-11-14
Epub
2006-00-06
Pages
17390-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1859939
Subset
IM
Grants
NINDS NIH HHS · P01 NS031492 · United States
NCI NIH HHS · R01 CA035675 · United States
NINDS NIH HHS · P01 NS31492 · United States
NCI NIH HHS · R01 CA35675 · United States
External Links
PubMed source DOI: 10.1073/pnas.0608386103 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2