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Potential Contribution to Antidiabetic Treatments of Epstein-Barr Virus Proteins LMP1 and EBNA1

Yıl 2018, Cilt: 2 Sayı: 3, 146 - 155, 21.12.2018

Öz

The prevalence and incidence of diabetes is a
global healthcare-management problem that is increasing almost every day. The
high numbers of complications make the diagnosis and treatment of diabetes
extremely important. Nowadays, it is believed that a large number of diseases,
including diabetes, are related to the Endoplasmic Reticulum (ER)
stress-induced apoptosis. Proliferative activity of Epstein-Barr Virus (EBV)
proteins occurs via
two
mediators Epstein-Barr Nuclear Antigen-1 (EBNA1) and Latent Membrane Protein-1
(LMP1). In this study, it was aimed to investigate the reversal of pancreatic
cell loss by applying recombinant viral EBV proteins. It has also been
investigated how related proteins can effect DNA damage, ER stress, and
contribute to insulin synthesis-release. For these targets, it has been decided
to use doses of 0.1 ppm and 0.5 ppm of commercially obtained recombinant EBNA1
and LMP1 proteins. The possible effects of these proteins on mRNA expression
levels of genes known to be responsible for the specified proliferation have
been investigated. In the study, DNA damage was analyzed by Comet Assay, and
Endoplasmic Reticulum stress was analyzed by Real Time RT-PCR. In RT-PCR
studies, mRNA expression levels of cell proliferation markers including PDX 1,
WNT 4, FoxO1, TCF7L2 and beta catenin genes in the EBNA1 group were increased
by 6.48, 4.25, 2.37, 3.8 and 1.4 times, respectively compared with control
group. At the end of the study; EBV recombinant proteins LMP1 and EBNA1 have
been shown to increase the expression levels of genes responsible for
proliferation. It has also been shown that related proteins may be advantageous
in reversing beta cell losses by suppressing the expression levels of ER
stress-inducing genes.
 It has been thought
that the use of viro-therapeutic agents in antidiabetic treatments may be
appropriate if supported by higher-level studies in this regard.

Kaynakça

  • 1.Müler N., Heller T., Freitag M.H., Gerste B., Haupt C. M., Wolf G. and Müller U.A. Healthcare utilization of people with type 2 diabetes in Germany: an analysis based on health insurance data. Diabetic Medicine vol. 32(7), pp. 951–957, 2015
  • 2. International Diabetes Federation. Diabetes Atlas. 4th Edition, Brussels, Belgium, 2009.
  • 3. (2011) The Republic of Turkey Ministry of Health General Directorate of Basic Health Services web site. [Online]. Avaliable: http://beslenme.gov.tr/content/files/yayinlar/kitaplar/diger_kitaplar/diyabet_kitap.pdf Accessed 20 June 2017
  • 4. EUROBIAB-ACE Study Group. Varition and trends in incidence of cihildhood Diabetes in Europe. Lancet vol. 355, pp. 873-876, 2000.
  • 5. Arman D. Epstein-Barr Virus. In Infeksiyon hastalıkları ve mikrobiyolojisi, ed. A. Topçu, G. Söyletir, M. Doğanay, Istanbul, Turkey, Nobel Publications, 2002
  • 6. Bonnet M., Guinebretiere J.M., Kremmer E., Grunewald V., Benhamou E. and Contesso G. Detection of Epstein-Barr virus in invasive breast cancer. Journal of the National Cancer Institute vol. 91(16) pp 1376–1381, 1999.
  • 7. Kutok J.L. and Wang F. Spectrum of Epstein-Barr Virus-Associated Diseases. Annual Review of Pathology. vol. 1, pp. 375–404, 2006.
  • 8. Nonkwelo C., Skinner J., Bell A., Rickinson A. and Sample J. Transcription start sites downstream of the Epstein-Barr virus (EBV) Fp promoter in early-passage Burkitt lymphoma cells defi ne a fourth promoter for expression of the EBV EBNA-1 protein. Journal of Virology vol 70, pp. 623–627, 1996.
  • 9. Doğan B. Tekrarlayan tonsillit hastalarının tonsil dokularında EBV’nin gerçek zamanlı polimeraz zincirleme reaksiyonu ile kantitatif tespiti ve serum VCA-IgG titreleri ile korelasyonu. Thesis. Gazi University Instutiın of Health Sciences, Ankara, Turkey, 2005.
  • 10. Yaung L.S. and Murray P.G. EBV and oncogenesis: from latent genes to tumours. Oncogene vol. 22, pp. 5108–5121, 2003.
  • 11. Izumi K.M. and Kieff E.D. The Epstein-Barr virus oncogene product latent membrane protein 1 engagesthe tumor necrosis factor receptor associated death domain protein to mediate B lymphocyte growth transformation and activate NF-kappa B. Proceedings of the National Academy of Sciences of the United States vol, 94 pp. 12592–12597, 1997.
  • 12. Zheng H., Li L., Hu D., Deng X. and Cao Y. Role of Epstein-Barr Virus encoded Latent Membrane Protein 1 in the carcinogenesis of nasopharyngeal carcinoma. Cellular &Molecular Immunology, vol. 4(3) pp. 185–196, 2007.
  • 13. Nicholas J.K. The Bradford Method For Protein Quantitation The Protein Protocols Handbook. Totowa, NJ: Humana Press Inc. 2009.
  • 14. Gou Y., Sun C., Hu L., He J., Zhang C., Feng Y., Zhang P., Kong X., Xiao L. and Li Y. Correlation between DNA damage and EB virus infection in nasopharyngeal carcinoma. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. Vol 30(2) pp. 184–187, 2014.
  • 15. Ju Y., Xu T., Zhang H. and Yu A. FOXO1-dependent DNA damage repair is regulated by JNK in lung cancer cells. International Journal of Oncology. Vol. 44(4) pp. 1284–1292, 2014.
  • 16. Hayakawa J., Depatia C., Ohmichi M. and Mercola D. The Activation of c-Jun NH2-terminal Kinase (JNK) by DNA-damaging Agents Serves to Promote Drug Resistance via Activating Transcription Factor 2 (ATF2) – dependent Enhanced DNA Repair. Journal of Biological Chemistry. Vol. 278, pp. 20582–205892, 2003.
  • 17. Tobiume K., Matsuzawa A., Takahashi T., Nishitoh H., Morita K., Takeda K., Minowa O., Miyazono K., Noda T. and Ichijo H.. ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Reports. vol 2(3) pp. 222–228, 2001.
  • 18. Laherty C., Hu H., Opipari A., Wang F. and Dixit V.. The Epstein- Barr virus LMP1 gene product induces A20 zinc fi nger protein expression by activating nuclear factor, KB. Journal of Biological Chemistry. Vol. 267, pp. 24157–24160, 1992.
  • 19. Rowe M., Peng-Pillon M., Huen D., Hardy R., Croom-Carter D., Lundgren E., Rickinson A.B. Up regulation of bcl-2 by the Epstein- Barr virus latent membrane protein LMP1: a B-cell specifi c response that is delayed relative to NF-KB Activation and to induction to cell surface markers. Journal of Virology, vol. 68 pp. 5602–5612, 1994.
  • 20. Tran T. M., Temkin V., Shi B., Pagliari L., Daniel S., Ferra C. and Pope R.M. TNF�-induced macrophage death via caspase-dependent and independent pathways. Apoptosis, vol. 14(3) pp. 320–322, 2009.
  • 21. De Leo A., Arena G., Stecca C., Raciti M. and Mattia E. Resveratrol inhibits proliferation and survival of Epstein Barr virus-infected Burkitt’s lymphoma cells depending on viral latency program. Molecular Cancer Research, vol. 9(10), pp. 1346–1355, 2011.
  • 22. Meier I., Shephard S. E. and Lutz W. K. Nitrosation of aspartic acid, aspartame, and glycine ethyl ester. Alkylation of 4-(p-nitrobenzyl)pyridine (NBP) in vitro and binding to DNA in therat. Mutation Research, vol. 238(3), pp. 193–201, 1990.
  • 23. Rudin M., Ben-Abraham R., Gazi V., Tendler V., Tashlykov V. and Katz Y. Single-dose ketamine administration induces apoptosis in neonatal mouse brain. Journal of Basic Clinical Physiology and Pharmacology, vol. 16(4) pp. 231–243, 2005.

Epstein-Barr Virus Proteinleri LMP1 ve EBNA1’in Antidiyabetik Tedavilere Potensiyel Katkısı

Yıl 2018, Cilt: 2 Sayı: 3, 146 - 155, 21.12.2018

Öz

Diyabet prevalansı ve insidansı her geçen gün artmaya devam eden global
bir sağlık problemidir. Diyabetik komplikasyonların sıklığı diyabet tanı ve
tedavisini önemli kılmaktadır. Günümüzde, diyabet de dahil olmak üzere çok
sayıda hastalığın Endoplazmik Retikülüm (ER) stres kaynaklı apoptoz ile
ilişkili olduğuna inanılmaktadır. Epstein-Barr virusun proliferatif etkinliği;
Epstein-Barr Nuclear
Antigen-1 (EBNA1) ve Latent Membrane Protein-1 (LMP1) adlı
iki mediatör protein
aracılığıyla olmaktadır. 
Bu çalışmada;
pankreatik beta hücre kayıplarının bertarafında 
iligili EBV proteinlerinin kullanılması amaçlanmıştır. Ayrıca ilgili
proteinlerin ER stresi, insulin sentez ve salınımı ve DNA hasarı üzerine
etkilerinin araştırılması hedeflenmiştir. Bu hedefler için, 0,1 ppm ve 0,5 ppm
dozlarında ticari olarak elde edilen rekombinant EBNA1 ve LMP1 proteinleri
kullanılmıştır. Bu proteinlerin proliferasyondan sorumlu olduğu bilinen
genlerin mRNA ekspresyon seviyeleri üzerindeki olası etkileri araştırılmıştır.
Çalışmada DNA hasarı Comet Assay ile, proliferasyon düzeyleri Real Time RT-PCR
ile analiz edilmiştir. RT-PCR çalışmasında, hücre proliferasyonundan sorumlu
oldukları bilinen PDX 1,WNT 4, FoxO1, TCF7L2 ve
 
beta katenin genlerinin mRNA ekpresyon düzeyleri control grubana nazaran
EBNA 1 grubunda sırasıyla 6.48, 4.25, 2.37, 3.8 ve 1.4 kat arttığı tespit
edilmiştir. Aynı zamanda ilgili proteinlerin ER stres kaynaklı genlerin
ekspresyon seviyelerini bastırarak beta hücre kayıplarını tersine çevirmek
açısından avantajlı olabileceği gösterilmiştir. Bu proteinlerin antidiyabetik
tedavilerde viro-terapötik ajan olarak kullanılması bu konuda daha üst düzey
çalışmalarla desteklenmeye muhtaçtır.

Kaynakça

  • 1.Müler N., Heller T., Freitag M.H., Gerste B., Haupt C. M., Wolf G. and Müller U.A. Healthcare utilization of people with type 2 diabetes in Germany: an analysis based on health insurance data. Diabetic Medicine vol. 32(7), pp. 951–957, 2015
  • 2. International Diabetes Federation. Diabetes Atlas. 4th Edition, Brussels, Belgium, 2009.
  • 3. (2011) The Republic of Turkey Ministry of Health General Directorate of Basic Health Services web site. [Online]. Avaliable: http://beslenme.gov.tr/content/files/yayinlar/kitaplar/diger_kitaplar/diyabet_kitap.pdf Accessed 20 June 2017
  • 4. EUROBIAB-ACE Study Group. Varition and trends in incidence of cihildhood Diabetes in Europe. Lancet vol. 355, pp. 873-876, 2000.
  • 5. Arman D. Epstein-Barr Virus. In Infeksiyon hastalıkları ve mikrobiyolojisi, ed. A. Topçu, G. Söyletir, M. Doğanay, Istanbul, Turkey, Nobel Publications, 2002
  • 6. Bonnet M., Guinebretiere J.M., Kremmer E., Grunewald V., Benhamou E. and Contesso G. Detection of Epstein-Barr virus in invasive breast cancer. Journal of the National Cancer Institute vol. 91(16) pp 1376–1381, 1999.
  • 7. Kutok J.L. and Wang F. Spectrum of Epstein-Barr Virus-Associated Diseases. Annual Review of Pathology. vol. 1, pp. 375–404, 2006.
  • 8. Nonkwelo C., Skinner J., Bell A., Rickinson A. and Sample J. Transcription start sites downstream of the Epstein-Barr virus (EBV) Fp promoter in early-passage Burkitt lymphoma cells defi ne a fourth promoter for expression of the EBV EBNA-1 protein. Journal of Virology vol 70, pp. 623–627, 1996.
  • 9. Doğan B. Tekrarlayan tonsillit hastalarının tonsil dokularında EBV’nin gerçek zamanlı polimeraz zincirleme reaksiyonu ile kantitatif tespiti ve serum VCA-IgG titreleri ile korelasyonu. Thesis. Gazi University Instutiın of Health Sciences, Ankara, Turkey, 2005.
  • 10. Yaung L.S. and Murray P.G. EBV and oncogenesis: from latent genes to tumours. Oncogene vol. 22, pp. 5108–5121, 2003.
  • 11. Izumi K.M. and Kieff E.D. The Epstein-Barr virus oncogene product latent membrane protein 1 engagesthe tumor necrosis factor receptor associated death domain protein to mediate B lymphocyte growth transformation and activate NF-kappa B. Proceedings of the National Academy of Sciences of the United States vol, 94 pp. 12592–12597, 1997.
  • 12. Zheng H., Li L., Hu D., Deng X. and Cao Y. Role of Epstein-Barr Virus encoded Latent Membrane Protein 1 in the carcinogenesis of nasopharyngeal carcinoma. Cellular &Molecular Immunology, vol. 4(3) pp. 185–196, 2007.
  • 13. Nicholas J.K. The Bradford Method For Protein Quantitation The Protein Protocols Handbook. Totowa, NJ: Humana Press Inc. 2009.
  • 14. Gou Y., Sun C., Hu L., He J., Zhang C., Feng Y., Zhang P., Kong X., Xiao L. and Li Y. Correlation between DNA damage and EB virus infection in nasopharyngeal carcinoma. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. Vol 30(2) pp. 184–187, 2014.
  • 15. Ju Y., Xu T., Zhang H. and Yu A. FOXO1-dependent DNA damage repair is regulated by JNK in lung cancer cells. International Journal of Oncology. Vol. 44(4) pp. 1284–1292, 2014.
  • 16. Hayakawa J., Depatia C., Ohmichi M. and Mercola D. The Activation of c-Jun NH2-terminal Kinase (JNK) by DNA-damaging Agents Serves to Promote Drug Resistance via Activating Transcription Factor 2 (ATF2) – dependent Enhanced DNA Repair. Journal of Biological Chemistry. Vol. 278, pp. 20582–205892, 2003.
  • 17. Tobiume K., Matsuzawa A., Takahashi T., Nishitoh H., Morita K., Takeda K., Minowa O., Miyazono K., Noda T. and Ichijo H.. ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Reports. vol 2(3) pp. 222–228, 2001.
  • 18. Laherty C., Hu H., Opipari A., Wang F. and Dixit V.. The Epstein- Barr virus LMP1 gene product induces A20 zinc fi nger protein expression by activating nuclear factor, KB. Journal of Biological Chemistry. Vol. 267, pp. 24157–24160, 1992.
  • 19. Rowe M., Peng-Pillon M., Huen D., Hardy R., Croom-Carter D., Lundgren E., Rickinson A.B. Up regulation of bcl-2 by the Epstein- Barr virus latent membrane protein LMP1: a B-cell specifi c response that is delayed relative to NF-KB Activation and to induction to cell surface markers. Journal of Virology, vol. 68 pp. 5602–5612, 1994.
  • 20. Tran T. M., Temkin V., Shi B., Pagliari L., Daniel S., Ferra C. and Pope R.M. TNF�-induced macrophage death via caspase-dependent and independent pathways. Apoptosis, vol. 14(3) pp. 320–322, 2009.
  • 21. De Leo A., Arena G., Stecca C., Raciti M. and Mattia E. Resveratrol inhibits proliferation and survival of Epstein Barr virus-infected Burkitt’s lymphoma cells depending on viral latency program. Molecular Cancer Research, vol. 9(10), pp. 1346–1355, 2011.
  • 22. Meier I., Shephard S. E. and Lutz W. K. Nitrosation of aspartic acid, aspartame, and glycine ethyl ester. Alkylation of 4-(p-nitrobenzyl)pyridine (NBP) in vitro and binding to DNA in therat. Mutation Research, vol. 238(3), pp. 193–201, 1990.
  • 23. Rudin M., Ben-Abraham R., Gazi V., Tendler V., Tashlykov V. and Katz Y. Single-dose ketamine administration induces apoptosis in neonatal mouse brain. Journal of Basic Clinical Physiology and Pharmacology, vol. 16(4) pp. 231–243, 2005.
Toplam 23 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Sağlık Kurumları Yönetimi
Bölüm Araştırma Makalesi
Yazarlar

Serkan ŞEN 0000-0002-2884-4753

Merve ŞEN

Mustafa ALTINDİŞ

Sefa ÇELİK

Korhan ALTUNBAŞ

İbrahim Hakkı CİĞERCİ

Yayımlanma Tarihi 21 Aralık 2018
Kabul Tarihi 14 Kasım 2018
Yayımlandığı Sayı Yıl 2018 Cilt: 2 Sayı: 3

Kaynak Göster

AMA ŞEN S, ŞEN M, ALTINDİŞ M, ÇELİK S, ALTUNBAŞ K, CİĞERCİ İH. Potential Contribution to Antidiabetic Treatments of Epstein-Barr Virus Proteins LMP1 and EBNA1. J Biotechnol and Strategic Health Res. Aralık 2018;2(3):146-155.
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