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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2012

Open Access 01-12-2012 | Research

Astrocyte elevated gene-1 regulates astrocyte responses to neural injury: implications for reactive astrogliosis and neurodegeneration

Authors: Neha Vartak-Sharma, Anuja Ghorpade

Published in: Journal of Neuroinflammation | Issue 1/2012

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Abstract

Background

Reactive astrogliosis is a ubiquitous but poorly understood hallmark of central nervous system pathologies such as trauma and neurodegenerative diseases. In vitro and in vivo studies have identified proinflammatory cytokines and chemokines as mediators of astrogliosis during injury and disease; however, the molecular mechanism remains unclear. In this study, we identify astrocyte elevated gene-1 (AEG-1), a human immunodeficiency virus 1 or tumor necrosis factor α-inducible oncogene, as a novel modulator of reactive astrogliosis. AEG-1 has engendered tremendous interest in the field of cancer research as a therapeutic target for aggressive tumors. However, little is known of its role in astrocytes and astrocyte-mediated diseases. Based on its oncogenic role in several cancers, here we investigate the AEG-1-mediated regulation of astrocyte migration and proliferation during reactive astrogliosis.

Methods

An in vivo brain injury mouse model was utilized to show AEG-1 induction following reactive astrogliosis. In vitro wound healing and cell migration assays following AEG-1 knockdown were performed to analyze the role of AEG-1 in astrocyte migration. AEG-1-mediated regulation of astrocyte proliferation was assayed by quantifying the levels of cell proliferation markers, Ki67 and proliferation cell nuclear antigen, using immunocytochemistry. Confocal microscopy was used to evaluate nucleolar localization of AEG-1 in cultured astrocytes following injury.

Results

The in vivo mouse model for brain injury showed reactive astrocytes with increased glial fibrillary acidic protein and AEG-1 colocalization at the wound site. AEG-1 knockdown in cultured human astrocytes significantly reduced astrocyte migration into the wound site and cell proliferation. Confocal analysis showed colocalization of AEG-1 to the nucleolus of injured cultured human astrocytes.

Conclusions

The present findings report for the first time the novel role of AEG-1 in mediating reactive astrogliosis and in regulating astrocyte responses to injury. We also report the nucleolar localization of AEG-1 in human astrocytes in response to injury. Future studies may be directed towards elucidating the molecular mechanism of AEG-1 action in astrocytes during reactive astrogliosis.
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Literature
1.
Kang DC, Su ZZ, Sarkar D, Emdad L, Volsky DJ, Fisher PB: Cloning and characterization of HIV-1-inducible astrocyte elevated gene-1, AEG-1. Gene 2005, 353:8–15.CrossRefPubMed
2.
Sun W, Fan YZ, Xi H, Lu XS, Ye C, Zhang JT: Astrocyte elevated gene-1 overexpression in human primary gallbladder carcinomas: an unfavorable and independent prognostic factor. Oncol Rep 2011, 26:1133–1142.PubMed
3.
Liao WT, Guo L, Zhong Y, Wu YH, Li J, Song LB: Astrocyte elevated gene-1 (AEG-1) is a marker for aggressive salivary gland carcinoma. J Transl Med 2011, 9:205.CrossRefPubMedPubMedCentral
4.
Chen W, Ke Z, Shi H, Yang S, Wang L: Overexpression of AEG-1 in renal cell carcinoma and its correlation with tumor nuclear grade and progression. Neoplasma 2010, 57:522–529.CrossRefPubMed
5.
Liu L, Wu J, Ying Z, Chen B, Han A, Liang Y, Song L, Yuan J, Li J, Li M: Astrocyte elevated gene-1 upregulates matrix metalloproteinase-9 and induces human glioma invasion. Cancer Res 2010, 70:3750–3759.CrossRefPubMed
6.
Xia Z, Zhang N, Jin H, Yu Z, Xu G, Huang Z: Clinical significance of astrocyte elevated gene-1 expression in human oligodendrogliomas. Clin Neurol Neurosurg 2010, 112:413–419.CrossRefPubMed
7.
8.
Emdad L, Sarkar D, Su ZZ, Randolph A, Boukerche H, Valerie K, Fisher PB: Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis. Cancer Res 2006, 66:1509–1516.CrossRefPubMed
9.
Thirkettle HJ, Girling J, Warren AY, Mills IG, Sahadevan K, Leung H, Hamdy F, Whitaker HC, Neal DE: LYRIC/AEG-1 is targeted to different subcellular compartments by ubiquitinylation and intrinsic nuclear localization signals. Clin Cancer Res 2009, 15:3003–3013.CrossRefPubMed
10.
Sarkar D, Park ES, Emdad L, Lee SG, Su ZZ, Fisher PB: Molecular basis of nuclear factor-kappaB activation by astrocyte elevated gene-1. Cancer Res 2008, 68:1478–1484.CrossRefPubMed
11.
Thirkettle HJ, Mills IG, Whitaker HC, Neal DE: Nuclear LYRIC/AEG-1 interacts with PLZF and relieves PLZF-mediated repression. Oncogene 2009, 28:3663–3670.CrossRefPubMed
12.
Yoo BK, Santhekadur PK, Gredler R, Chen D, Emdad L, Bhutia S, Pannell L, Fisher PB, Sarkar D: Increased RNA-induced silencing complex (RISC) activity contributes to hepatocellular carcinoma. Hepatology 2011, 53:1538–1548.CrossRefPubMedPubMedCentral
13.
Ash SC, Yang DQ, Britt DE: LYRIC/AEG-1 overexpression modulates BCCIPalpha protein levels in prostate tumor cells. Biochem Biophys Res Commun 2008, 371:333–338.CrossRefPubMedPubMedCentral
14.
Aschner M: Immune and inflammatory responses in the CNS: modulation by astrocytes. Toxicol Lett 1998, 102–103:283–287.CrossRefPubMed
15.
16.
Farina C, Aloisi F, Meinl E: Astrocytes are active players in cerebral innate immunity. Trends Immunol 2007, 28:138–145.CrossRefPubMed
17.
Eddleston M, Mucke L: Molecular profile of reactive astrocytes-implications for their role in neurologic disease. Neuroscience 1993, 54:15–36.CrossRefPubMed
18.
19.
Maragakis NJ, Rothstein JD: Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2006, 2:679–689.CrossRefPubMed
20.
Barai S, Bandopadhayaya GP, Julka PK, Naik KK, Haloi AK, Kumar R, Seith A, Malhotra A: Role of Tc-glucoheptonic acid brain single photon emission computed tomography in differentiation of recurrent brain tumour and post-radiation gliosis. Australas Radiol 2004, 48:296–301.CrossRefPubMed
21.
Bigio EH, Colvin SM, Mickey BE, White CL 3rd: Rushing EJ: radiation change versus recurrent astrocytoma: diagnostic utility of the proliferation index? J Neurooncol 1999, 41:55–63.CrossRefPubMed
22.
Raore B, Schniederjan M, Prabhu R, Brat DJ, Shu HK, Olson JJ: Metastasis infiltration: an investigation of the postoperative brain-tumor interface. Int J Radiat Oncol Biol Phys 2011, 81:1075–1080.CrossRefPubMed
23.
Liu JM, Mao BY, Hong S, Liu YH, Wang XJ: The postoperative brain tumour stem cell (BTSC) niche and cancer recurrence. Adv Ther 2008, 25:389–398.CrossRefPubMed
24.
Burger PC, Dubois PJ, Schold SC Jr, Smith KR Jr, Odom GL, Crafts DC, Giangaspero F: Computerized tomographic and pathologic studies of the untreated, quiescent, and recurrent glioblastoma multiforme. J Neurosurg 1983, 58:159–169.CrossRefPubMed
25.
Gaspar LE, Fisher BJ, Macdonald DR, LeBer DV, Halperin EC, Schold SC Jr, Cairncross JG: Supratentorial malignant glioma: patterns of recurrence and implications for external beam local treatment. Int J Radiat Oncol Biol Phys 1992, 24:55–57.CrossRefPubMed
26.
Mitchell P, Ellison DW, Mendelow AD: Surgery for malignant gliomas: mechanistic reasoning and slippery statistics. Lancet Neurol 2005, 4:413–422.CrossRefPubMed
27.
Rolls A, Shechter R, Schwartz M: The bright side of the glial scar in CNS repair. Nat Rev Neurosci 2009, 10:235–241.CrossRefPubMed
28.
Jeon HY, Choi M, Howlett EL, Vozhilla N, Yoo BK, Lloyd JA, Sarkar D, Lee SG, Fisher PB: Expression patterns of astrocyte elevated gene-1 (AEG-1) during development of the mouse embryo. Gene Expr Patterns 2010, 10:361–367.CrossRefPubMedPubMedCentral
29.
Dou H, Grotepas CB, McMillan JM, Destache CJ, Chaubal M, Werling J, Kipp J, Rabinow B, Gendelman HE: Macrophage delivery of nanoformulated antiretroviral drug to the brain in a murine model of neuroAIDS. J Immunol 2009, 183:661–669.CrossRefPubMedPubMedCentral
30.
Gardner J, Borgmann K, Deshpande MS, Dhar A, Wu L, Persidsky R, Ghorpade A: Potential mechanisms for astrocyte-TIMP-1 downregulation in chronic inflammatory diseases. J Neurosci Res 2006, 83:1281–1292.CrossRefPubMed
31.
Chadderton T, Wilson C, Bewick M, Gluck S: Evaluation of three rapid RNA extraction reagents: relevance for use in RT-PCRs and measurement of low level gene expression in clinical samples. Cell Mol Biol (Noisy-le-grand) 1997, 43:1227–1234.
32.
Hidalgo K, Rojas IG, Penissi AB, Rudolph MI: TNFalpha increases in vitro migration of human HPV18-positive SW756 cervical carcinoma cells. Biocell 2005, 29:303–311.PubMed
33.
Levison SW, Jiang FJ, Stoltzfus OK, Ducceschi MH: IL-6-type cytokines enhance epidermal growth factor-stimulated astrocyte proliferation. Glia 2000, 32:328–337.CrossRefPubMed
34.
Neary JT, Zimmermann H: Trophic functions of nucleotides in the central nervous system. Trends Neurosci 2009, 32:189–198.CrossRefPubMed
35.
Gadea A, Schinelli S, Gallo V: Endothelin-1 regulates astrocyte proliferation and reactive gliosis via a JNK/c-Jun signaling pathway. J Neurosci 2008, 28:2394–2408.CrossRefPubMedPubMedCentral
36.
37.
John GR, Lee SC, Brosnan CF: Cytokines: powerful regulators of glial cell activation. Neuroscientist 2003, 9:10–22.CrossRefPubMed
38.
Correa-Cerro LS, Mandell JW: Molecular mechanisms of astrogliosis: new approaches with mouse genetics. J Neuropathol Exp Neurol 2007, 66:169–176.CrossRefPubMed
39.
Lovatt D, Sonnewald U, Waagepetersen HS, Schousboe A, He W, Lin JH, Han X, Takano T, Wang S, Sim FJ, Goldman SA, Nedergaard M: The transcriptome and metabolic gene signature of protoplasmic astrocytes in the adult murine cortex. J Neurosci 2007, 27:12255–12266.CrossRefPubMed
40.
Yoo BK, Emdad L, Su ZZ, Villanueva A, Chiang DY, Mukhopadhyay ND, Mills AS, Waxman S, Fisher RA, Llovet JM, Fisher PB, Sarkar D: Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression. J Clin Invest 2009, 119:465–477.CrossRefPubMedPubMedCentral
41.
Li J, Yang L, Song L, Xiong H, Wang L, Yan X, Yuan J, Wu J, Li M: Astrocyte elevated gene-1 is a proliferation promoter in breast cancer via suppressing transcriptional factor FOXO1. Oncogene 2009, 28:3188–3196.CrossRefPubMed
42.
Yu C, Chen K, Zheng H, Guo X, Jia W, Li M, Zeng M, Li J, Song L: Overexpression of astrocyte elevated gene-1 (AEG-1) is associated with esophageal squamous cell carcinoma (ESCC) progression and pathogenesis. Carcinogenesis 2009, 30:894–901.CrossRefPubMed
43.
John GR, Lee SC, Song X, Rivieccio M, Brosnan CF: IL-1-regulated responses in astrocytes: relevance to injury and recovery. Glia 2005, 49:161–176.CrossRefPubMed
44.
Daginakatte GC, Gadzinski A, Emnett RJ, Stark JL, Gonzales ER, Yan P, Lee JM, Cross AH, Gutmann DH: Expression profiling identifies a molecular signature of reactive astrocytes stimulated by cyclic AMP or proinflammatory cytokines. Exp Neurol 2008, 210:261–267.CrossRefPubMed
45.
Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kuncl RW, Kanai Y, Hediger MA, Wang Y, Schielke JP, Welty DF: Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron 1996, 16:675–686.CrossRefPubMed
46.
Park E, Velumian AA, Fehlings MG: The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. J Neurotrauma 2004, 21:754–774.CrossRefPubMed
47.
Lauriat TL, McInnes LA: EAAT2 regulation and splicing: relevance to psychiatric and neurological disorders. Mol Psychiatry 2007, 12:1065–1078.CrossRefPubMed
48.
Lee SG, Kim K, Kegelman TP, Dash R, Das SK, Choi JK, Emdad L, Howlett EL, Jeon HY, Su ZZ, Yoo BK, Sarkar D, Kim SH, Kang DC, Fisher PB: Oncogene AEG-1 promotes glioma-induced neurodegeneration by increasing glutamate excitotoxicity. Cancer Res 2011, 71:6514–6523.CrossRefPubMedPubMedCentral
49.
50.
Wilhelmsson U, Li L, Pekna M, Berthold CH, Blom S, Eliasson C, Renner O, Bushong E, Ellisman M, Morgan TE, Pekny M: Absence of glial fibrillary acidic protein and vimentin prevents hypertrophy of astrocytic processes and improves post-traumatic regeneration. J Neurosci 2004, 24:5016–5021.CrossRefPubMed
51.
Brambilla R, Bracchi-Ricard V, Hu WH, Frydel B, Bramwell A, Karmally S, Green EJ, Bethea JR: Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med 2005, 202:145–156.CrossRefPubMedPubMedCentral
52.
Emdad L, Sarkar D, Su ZZ, Lee SG, Kang DC, Bruce JN, Volsky DJ, Fisher PB: Astrocyte elevated gene-1: recent insights into a novel gene involved in tumor progression, metastasis and neurodegeneration. Pharmacol Ther 2007, 114:155–170.CrossRefPubMedPubMedCentral
53.
Qian BJ, Yan F, Li N, Liu QL, Lin YH, Liu CM, Luo YP, Guo F, Li HZ: MTDH/AEG-1-based DNA vaccine suppresses lung metastasis and enhances chemosensitivity to doxorubicin in breast cancer. Cancer Immunol Immunother 2011, 60:883–893.CrossRefPubMed
54.
Li X, Kong X, Huo Q, Guo H, Yan S, Yuan C, Moran MS, Shao C, Yang Q: Metadherin enhances the invasiveness of breast cancer cells by inducing epithelial to mesenchymal transition. Cancer Sci 2011, 102:1151–1157.CrossRefPubMed
55.
Kikuno N, Shiina H, Urakami S, Kawamoto K, Hirata H, Tanaka Y, Place RF, Pookot D, Majid S, Igawa M, Dahiya R: Knockdown of astrocyte-elevated gene-1 inhibits prostate cancer progression through upregulation of FOXO3a activity. Oncogene 2007, 26:7647–7655.CrossRefPubMed
56.
Kordek R, Biernat W, Alwasiak J, Liberski PP: Proliferating cell nuclear antigen (PCNA) and Ki-67 immunopositivity in human astrocytic tumours. Acta Neurochir (Wien) 1996, 138:509–512.CrossRef
57.
58.
Ochs RL, Lischwe MA, Spohn WH, Busch H: Fibrillarin: a new protein of the nucleolus identified by autoimmune sera. Biol Cell 1985, 54:123–133.CrossRefPubMed
59.
Pellizzoni L, Baccon J, Charroux B, Dreyfuss G: The survival of motor neurons (SMN) protein interacts with the snoRNP proteins fibrillarin and GAR1. Curr Biol 2001, 11:1079–1088.CrossRefPubMed
60.
Hernandez-Verdun D, Roussel P, Thiry M, Sirri V, Lafontaine DL: The nucleolus: structure/function relationship in RNA metabolism. Wiley Interdiscip Rev RNA 2010, 1:415–431.CrossRefPubMed
61.
Pestov DG, Strezoska Z, Lau LF: Evidence of p53-dependent cross-talk between ribosome biogenesis and the cell cycle: effects of nucleolar protein Bop1 on G(1)/S transition. Mol Cell Biol 2001, 21:4246–4255.CrossRefPubMedPubMedCentral
62.
63.
Meng X, Zhu D, Yang S, Wang X, Xiong Z, Zhang Y, Brachova P, Leslie KK: Cytoplasmic Metadherin (MTDH) provides survival advantage under conditions of stress by acting as RNA-binding protein. J Biol Chem 2012, 287:4485–4491.CrossRefPubMed
64.
Sabri F, Titanji K, De Milito A, Chiodi F: Astrocyte activation and apoptosis: their roles in the neuropathology of HIV infection. Brain Pathol 2003, 13:84–94.CrossRefPubMed
65.
Ghorpade A, Holter S, Borgmann K, Persidsky R, Wu L: HIV-1 and IL-1 beta regulate Fas ligand expression in human astrocytes through the NF-kappa B pathway. J Neuroimmunol 2003, 141:141–149.CrossRefPubMed
66.
Lee SG, Su ZZ, Emdad L, Sarkar D, Fisher PB: 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 U S A 2006, 103:17390–17395.CrossRefPubMedPubMedCentral
67.
Noch E, Bookland M, Khalili K: Astrocyte-elevated gene-1 (AEG-1) induction by hypoxia and glucose deprivation in glioblastoma. Cancer Biol Ther 2011, 11:32–39.CrossRefPubMedPubMedCentral
68.
Khuda II, Koide N, Noman AS, Dagvadorj J, Tumurkhuu G, Naiki Y, Komatsu T, Yoshida T, Yokochi T: Astrocyte elevated gene-1 (AEG-1) is induced by lipopolysaccharide as Toll-like receptor 4 (TLR4) ligand and regulates TLR4 signalling. Immunology 2009, 128:e700–706.CrossRefPubMedPubMedCentral
Metadata
Title
Astrocyte elevated gene-1 regulates astrocyte responses to neural injury: implications for reactive astrogliosis and neurodegeneration
Authors
Neha Vartak-Sharma
Anuja Ghorpade
Publication date
01-12-2012
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2012
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-9-195

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