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PMID: 7769701 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

The Epstein-Barr virus latent membrane protein 1 induces expression of the epidermal growth factor receptor.

Journal of virology ·Vol. 69 ·No. 7 ·1995-07-00 ·Pages 4390-8

Miller WE, Earp HS, Raab-Traub N

Abstract

The Epstein-Barr virus (EBV)-encoded LMP1 protein is an important component of the process of transformation by EBV. LMP1 is essential for transformation of B lymphocytes, most likely because of its profound effects on cellular gene expression. Although LMP1 is expressed in the majority of nasopharyngeal carcinoma (NPC) tumors, the effect of LMP1 on cellular gene expression and its contribution to the development of malignancy in epithelial cells is largely unknown. In this study the effects of LMP1 on the expression and tyrosine kinase activity of the epidermal growth factor receptor (EGFR) were investigated in C33A human epithelial cells. Stable or transient expression of LMP1 in C33A cells increased expression of the EGFR at both the protein and mRNA levels. In contrast, expression of the EGFR was not induced by LMP1 in EBV-infected B lymphocytes. Stimulation of LMP1-expressing C33A cells with epidermal growth factor (EGF) caused rapid tyrosine phosphorylation of the EGFR (pp170) as well as several other proteins, including pp120, pp85, pp75, and pp55, indicating that the EGFR induced by LMP1 is functional. LMP1 also induced expression of the A20 gene in C33A epithelial cells. In C33A cells, LMP1 expression increased the proliferative response to EGF, as LMP1-expressing C33A cells continued to increase in number when plated in serum-free media supplemented with EGF, while the neo control cells exhibited very low levels of viability and did not proliferate. Immunoblot analysis of protein extracts from nude mouse-passaged NPC tumors also demonstrated that the EGFR is overexpressed in primary NPC tumors as well as those passaged in nude mice. This study suggests that the alteration in the growth patterns of C33A cells expressing LMP1 is a result of increased proliferative signals due to enhanced EGFR expression, as well as protection from cell death due to LMP1-induced A20 expression. The induction of EGFR and A20 by LMP1 may be an important component of EBV infection in epithelial cells and could contribute to the development of epithelial malignancies such as NPC.

MeSH Terms
Cell Division Cell Line Enzyme Activation ErbB Receptors/biosynthesis,metabolism Herpesvirus 4, Human/genetics Humans Lymphocytes/metabolism,virology Nasopharyngeal Neoplasms/metabolism,virology Oncogenes RNA, Messenger/analysis Viral Matrix Proteins/genetics,physiology
Chemicals
EBV-associated membrane antigen, Epstein-Barr virus RNA, Messenger Viral Matrix Proteins ErbB Receptors
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Miller W E
Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill 27599-7295, USA.
Earp H S
Raab-Traub N
References (61)
61 references, click to expand
  1. Structure and localization of genes encoding aberrant and normal epidermal growth factor receptor RNAs from A431 human carcinoma cells.
    Mol Cell Biol. 1985 Jul;5(7):1722-34 PMID: 2991749
  2. The bovine papillomavirus E5 transforming protein can stimulate the transforming activity of EGF and CSF-1 receptors.
    Cell. 1989 Oct 6;59(1):21-32 PMID: 2551505
  3. All three domains of the Epstein-Barr virus-encoded latent membrane protein LMP-1 are required for transformation of rat-1 fibroblasts.
    J Virol. 1993 Mar;67(3):1638-46 PMID: 8382313
  4. Expression of the Epstein-Barr virus BamHI A fragment in nasopharyngeal carcinoma: evidence for a viral protein expressed in vivo.
    J Virol. 1991 Nov;65(11):6252-9 PMID: 1656092
  5. Effects of epidermal growth factor receptor concentration on tumorigenicity of A431 cells in nude mice.
    Cancer Res. 1986 Sep;46(9):4701-5 PMID: 3015393
  6. The Epstein-Barr virus 3.5-kilobase latent membrane protein 1 mRNA initiates from a TATA-Less promoter within the first terminal repeat.
    J Virol. 1995 Jul;69(7):4577-81 PMID: 7769727
  7. Epidermal growth factor.
    J Biol Chem. 1990 May 15;265(14):7709-12 PMID: 2186024
  8. Characterization of epidermal growth factor receptor gene expression in malignant and normal human cell lines.
    Proc Natl Acad Sci U S A. 1984 Dec;81(23):7308-12 PMID: 6095284
  9. Autophosphorylation sites on the epidermal growth factor receptor.
    Nature. 1984 Oct 4-10;311(5985):483-5 PMID: 6090945
  10. Epstein-Barr virus latent membrane protein (LMP1) and nuclear proteins 2 and 3C are effectors of phenotypic changes in B lymphocytes: EBNA-2 and LMP1 cooperatively induce CD23.
    J Virol. 1990 May;64(5):2309-18 PMID: 2157887
  11. Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor.
    Mol Cell Biol. 1994 Aug;14(8):5192-201 PMID: 7518560
  12. A multidrug-resistant MCF-7 human breast cancer cell line which exhibits cross-resistance to antiestrogens and hormone-independent tumor growth in vivo.
    Mol Endocrinol. 1988 Oct;2(10):886-92 PMID: 3185565
  13. Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation.
    Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9150-4 PMID: 8415670
  14. The transforming domain alone of the latent membrane protein of Epstein-Barr virus is toxic to cells when expressed at high levels.
    J Virol. 1989 Jun;63(6):2469-75 PMID: 2542565
  15. Epstein-Barr virus gene expression in nasopharyngeal carcinoma.
    J Gen Virol. 1988 May;69 ( Pt 5):1051-65 PMID: 2836550
  16. Protein phosphorylation at tyrosine is induced by the v-erbB gene product in vivo and in vitro.
    Cell. 1985 Mar;40(3):609-18 PMID: 2982500
  17. Consistent transcription of the Epstein-Barr virus LMP2 gene in nasopharyngeal carcinoma.
    J Virol. 1992 May;66(5):3257-62 PMID: 1313931
  18. A novel effect of EGF on mRNA stability.
    Nucleic Acids Res. 1988 Jun 10;16(11):4957-66 PMID: 3260374
  19. Contributory effects of de novo transcription and premature transcript termination in the regulation of human epidermal growth factor receptor proto-oncogene RNA synthesis.
    J Biol Chem. 1991 Jan 25;266(3):1746-53 PMID: 1988448
  20. Epidermal-growth-factor-dependent transformation by a human EGF receptor proto-oncogene.
    Science. 1987 Dec 4;238(4832):1408-10 PMID: 3500513
  21. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells.
    Cell. 1985 Dec;43(3 Pt 2):831-40 PMID: 3000618
  22. Oncogenes and signal transduction.
    Cell. 1991 Jan 25;64(2):281-302 PMID: 1846320
  23. Characterization, quantification, and potential clinical value of the epidermal growth factor receptor in head and neck squamous cell carcinomas.
    Head Neck. 1991 Mar-Apr;13(2):132-9 PMID: 2022478
  24. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor.
    Cell. 1993 May 7;73(3):611-20 PMID: 8490966
  25. The Epstein-Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family.
    Cell. 1995 Feb 10;80(3):389-99 PMID: 7859281
  26. Transforming capacities of avian erythroblastosis virus mutants deleted in the erbA or erbB oncogenes.
    Cell. 1983 Jan;32(1):227-38 PMID: 6297784
  27. Epstein-Barr virus latent membrane protein transactivates the human immunodeficiency virus type 1 long terminal repeat through induction of NF-kappa B activity.
    J Virol. 1992 Nov;66(11):6496-501 PMID: 1404600
  28. Chromatin structure of the EGFR gene suggests a role for intron 1 sequences in its regulation in breast cancer cells.
    Nucleic Acids Res. 1993 Dec 11;21(24):5736-41 PMID: 8284222
  29. Novel transcription from the Epstein-Barr virus terminal EcoRI fragment, DIJhet, in a nasopharyngeal carcinoma.
    J Virol. 1990 Oct;64(10):4948-56 PMID: 2168978
  30. The multiple membrane-spanning segments of the BNLF-1 oncogene from Epstein-Barr virus are required for transformation.
    Oncogene. 1989 Jan;4(1):67-74 PMID: 2536919
  31. Epstein-Barr virus nuclear proteins EBNA-3A and EBNA-3C are essential for B-lymphocyte growth transformation.
    J Virol. 1993 Apr;67(4):2014-25 PMID: 8445720
  32. Morphological transformation of human keratinocytes expressing the LMP gene of Epstein-Barr virus.
    Nature. 1990 May 31;345(6274):447-9 PMID: 1692971
  33. The Epstein-Barr virus LMP1 gene product induces A20 zinc finger protein expression by activating nuclear factor kappa B.
    J Biol Chem. 1992 Dec 5;267(34):24157-60 PMID: 1332946
  34. Phosphatidylinositol 3-kinase activation is mediated by high-affinity interactions between distinct domains within the p110 and p85 subunits.
    Mol Cell Biol. 1994 Jan;14(1):42-9 PMID: 8264609
  35. Human tumor cell lines with EGF receptor gene amplification in the absence of aberrant sized mRNAs.
    Nucleic Acids Res. 1985 Dec 9;13(23):8477-86 PMID: 3001641
  36. Epidermal growth factor stimulates tyrosine phosphorylation in the neonatal mouse: association of a M(r) 55,000 substrate with the receptor.
    Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8477-81 PMID: 1382290
  37. Epidermal growth factor receptor expression and function control cytotoxic responsiveness to tumor necrosis factor in ME-180 squamous carcinoma cells.
    Cell Growth Differ. 1993 May;4(5):411-9 PMID: 8518234
  38. Epstein-Barr virus nuclear protein 2 is a key determinant of lymphocyte transformation.
    Proc Natl Acad Sci U S A. 1989 Dec;86(23):9558-62 PMID: 2556717
  39. The E5 oncoprotein of human papillomavirus type 16 transforms fibroblasts and effects the downregulation of the epidermal growth factor receptor in keratinocytes.
    J Virol. 1993 Aug;67(8):4521-32 PMID: 8392596
  40. The differentiated form of nasopharyngeal carcinoma contains Epstein-Barr virus DNA.
    Int J Cancer. 1987 Jan 15;39(1):25-9 PMID: 3025109
  41. Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases.
    Nature. 1992 Dec 17;360(6405):689-92 PMID: 1465135
  42. Epithelial-specific keratin gene expression: identification of a 300 base-pair controlling segment.
    Nucleic Acids Res. 1990 Jan 25;18(2):247-53 PMID: 1691483
  43. Epidermal growth factor receptor gene promoter. Deletion analysis and identification of nuclear protein binding sites.
    J Biol Chem. 1988 Apr 25;263(12):5693-9 PMID: 2833511
  44. Epstein-Barr virus latent membrane protein inhibits human epithelial cell differentiation.
    Nature. 1990 Apr 19;344(6268):777-80 PMID: 2158628
  45. A Ca2+/calmodulin-dependent protein kinase, CaM kinase-Gr, expressed after transformation of primary human B lymphocytes by Epstein-Barr virus (EBV) is induced by the EBV oncogene LMP1.
    J Virol. 1994 Mar;68(3):1697-705 PMID: 8107230
  46. Involvement of Shc in insulin- and epidermal growth factor-induced activation of p21ras.
    Mol Cell Biol. 1994 Mar;14(3):1575-81 PMID: 8114695
  47. Trans-activation of epidermal growth factor receptor gene by the hepatitis B virus X-gene product.
    Virology. 1993 Oct;196(2):878-82 PMID: 8396816
  48. SH2 and SH3 domains.
    Curr Biol. 1993 Jul 1;3(7):434-42 PMID: 15335710
  49. Expression of LMP1 in epithelial cells leads to the activation of a select subset of NF-kappa B/Rel family proteins.
    J Virol. 1995 Jul;69(7):4572-6 PMID: 7769726
  50. EGF receptor in neoplasia and metastasis.
    Cancer Metastasis Rev. 1993 Sep;12(3-4):255-74 PMID: 8281612
  51. Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease.
    N Engl J Med. 1989 Oct 19;321(16):1080-5 PMID: 2552313
  52. Upregulation of bcl-2 by the Epstein-Barr virus latent membrane protein LMP1: a B-cell-specific response that is delayed relative to NF-kappa B activation and to induction of cell surface markers.
    J Virol. 1994 Sep;68(9):5602-12 PMID: 7520093
  53. EBV gene expression in an NPC-related tumour.
    EMBO J. 1989 Sep;8(9):2639-51 PMID: 2479554
  54. Increased epidermal growth factor receptor gene expression by gamma-interferon in a human breast carcinoma cell line.
    Br J Cancer. 1991 Jul;64(1):64-8 PMID: 1906727
  55. Expression of Ki67 antigen, epidermal growth factor receptor and Epstein-Barr virus-encoded latent membrane protein (LMP1) in nasopharyngeal carcinoma.
    Eur J Cancer B Oral Oncol. 1994 Sep;30B(5):290-5 PMID: 7703798
  56. Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death.
    Cell. 1991 Jun 28;65(7):1107-15 PMID: 1648447
  57. Cloning of PI3 kinase-associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases.
    Cell. 1991 Apr 5;65(1):83-90 PMID: 1849461
  58. Expression of Epstein-Barr virus-encoded proteins in nasopharyngeal carcinoma.
    Int J Cancer. 1988 Sep 15;42(3):329-38 PMID: 2843473
  59. The A20 zinc finger protein protects cells from tumor necrosis factor cytotoxicity.
    J Biol Chem. 1992 Jun 25;267(18):12424-7 PMID: 1618749
  60. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells.
    Nature. 1984 May 31-Jun 6;309(5967):418-25 PMID: 6328312
  61. Close similarity of epidermal growth factor receptor and v-erb-B oncogene protein sequences.
    Nature. 1984 Feb 9-15;307(5951):521-7 PMID: 6320011
Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/JVI.69.7.4390-4398.1995
Published
1995-07-00
Pages
4390-8
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC189180
Subset
IM
Grants
NCI NIH HHS · CA19014 · United States
NCI NIH HHS · CA32979 · United States
NCI NIH HHS · CA52406 · United States
External Links
PubMed source DOI: 10.1128/JVI.69.7.4390-4398.1995 PMC Full Text View journal details
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