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Endoplazmik Retikulum Stresinde Hücre Sağkalım ve Ölüm Kararı

Year 2016, Volume: 6 Issue: 2, 0 - 0, 24.06.2016

Abstract

Endoplazmik Retikulum (ER) ’un fonksiyonları protein ve lipid biyosentezi, protein katlanması ve trafiği, kalsiyum homeostazı ve çeşitli diğer yaşamsal süreçlerdir. ER ’de yanlış katlanmış ya da katlanmamış proteinlerin birikimi ER homeostazında değişikliklere yol açar. ER fonksiyonlarını hasara uğratan hücresel durumlar olduğunda, ER stresi meydana gelir ve sonuç olarak katlanmamış protein yanıtı (UPR) olarak isimlendirilen bir yolak aktive olur. UPR sinyal yolağı ER şaperonlarının miktarını artırır ve protein translasyonunu düzenler. UPR iki zıt fonksiyona sahiptir: ilki ER homeostazını yeniden sağlamak ve ikincisi apoptozisin ya da otofajinin uyarılmasını içeren adaptif mekanizmalar geliştirmek. UPR stres koşullarının üstesinden gelemezse, üçüncü bir yol olarak hücrenin sağkalımı ve büyümesine de izin verebilir. Sonuç olarak, metabolik hastalıklar, nörodejeneratif hastalıklar, inflamatuar hastalıklar ve kanser meydana gelebilir. ( Sakarya Tıp Dergisi 2016, 6(2):73-80 )

Anahtar Kelimeler: ER stres, katlanmamış protein yanıtı, apoptozis, otofaji

References

  • Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta. 2013; 1833(12):3460-70. 2. Ni M, Lee AS. ER chaperones in mammalian development and human diseases. FEBS Lett. 2007; 581(19):3641-51. 3. Zhang X, Xu C, Yu C, Chen W, Li Y. Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol. 2014; 21; 20(7): 17681776. 4. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nature, Molecular Cell Bıology. 2007; 8,519-529. 5. Bravo R, Parra V, Gatica D, Rodriguez AE, Torrealba N, Paredes F, Wang ZV, et al. Endoplasmic reticulum and the unfolded protein response: dynamics and metabolic integration. Int Rev Cell Mol Biol. 2013; 301:215-90. 6. Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov. 2008; 7,1013–1030. 7. Kampinga HH, Craig EA. The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat.Rev.Mol. CellBiol. 2010; 11, 579–592. 8. Appenzeller-Herzog C, Ellgaard L. The human PDI family: versatility packed into a single fold. Biochim.Biophys.Acta. 2008; 1783: 535–548. 9. Rutkevich LA, Williams DB. Participation of lectin chaperones and thiol oxido reductases in protein folding within the endoplasmic reticulum. Cell. Biol. 2011; 23,157– 166. 10. Bukau B, Weissman J, Horwich A. Molecular chaperones and protein quality control. Cell. 2006; 125, 443–451. 11. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010; 140:900–917. 12. Roussel BD, Kruppa AJ, Miranda E, Crowther DC, Lomas DA, Marciniak SJ. Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol. 2013; 12: 105–18. 13. Schröder M, Kaufman RJ. The mammalian unfolded protein response. Annual Review of Biochemistry. 2005; 74: 739–789. 14. Wang W, Groenendyk J, Michalak M. Endoplasmic reticulum stress associated responses in cancer. Biochimica et Biophysica. 2014; 1843(10):2143-9. 15. Wang S, Kaufman RJ. The impact of the unfolded protein response on human disease. J. Cell Biol. 2012; 197(7):85767. 16. Todd DJ, Lee AH, Glimcher LH. The endoplasmic reticulum stress response in immunity and autoimmunity. Nat Rev Immunol. 2008; 8(9):663-74. 17. Vincenz L, Jäger R, O'Dwyer M, Samali A. Endoplasmic reticulum stress and the unfolded protein response: targeting the Achilles heel of multiple myeloma. Mol Cancer Ther. 2013 Jun;12(6):831-43. 18. Kaufman RJ. Orchestrating the unfolded protein response in health and disease. J. Clin. Invest. 2002; 110: 1389–
  • 19. Maurel M, Chevet E. Endoplasmic reticulum stress signaling: the microRNA connection. Am J Physiol Cell Physiol. 2013; 304: C1117–C1126. 20. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003;11:619–633. 21. Hinnebusch AG, Natarajan K. Gcn4p, a master regulator of gene expression, is controlled at multiple levels by diverse signals of starvation and stress. Eukaryot. Cell. 2002; 1, 22–32. 22. Lu PD, Harding HP, Ron D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J. Cell Biol. 2004; 167, 27–33. 23. Vattem KM, Wek RC. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc. Natl. Acad. Sci. 2004; 101, 11269. 24. Cao SS, Kaufman RJ. Unfolded protein response. Current Biology. 2012; 22(16). 25. Verfaillie T, Salazar M, Velasco G, Agostinis P. Linking ER Stress to Autophagy: Potential Implications for Cancer Therapy. Int J Cell Biol. 2010;2010:930509. 26. Shamu CE, Walter P. Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J. 1996; 153028–3039. 27. Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2004; 11,381–389. 28. Hetz C, Martinon F, Rodriguez D, Glimcher LH.The unfolded protein response: integrating stress signals through the stress sensor IRE1↓. Physiol Rev. 2011; 91: 1219–1243. 29. Sidrauski C, and Walter P. The transmembrane kinase IRE1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell. 1997; 90,1031–1039. 30. Yoshida H, Haze K, Yanagi H, Yura T, Mori K. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors.The Journal of biological chemistry. 1998; 273:33741–33749. 31. Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS, Goldstein JL. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell. 2000; 6:1355–1364. 32. Haze K, Yoshida H, Yanagi H, Yura T, Mori K. Mol Biol Cell. 1999; 10:3787–3799. 33. Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R,Nagata K, Harding HP, Ron D. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes&development. 2004; 18:3066-3077. 34. Ron D, Hubbard SR. How IRE1 reacts to ER stress. Cell. 2008; 132, 24–26. 35. Deng X, Xiao L, Lang W, Gao F, Ruvolo P, May Jr. WS. Novel role for JNK as a stress-activated Bcl2 kinase. J. Biol. Chem. 2001; 276:23681–23688. 36. Lei K, Davis RJ. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc. Natl. Acad. Sci. 2003; 100,2432–2437. 37. Yamaguchi H, Wang HG. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J. Biol. Chem. 2004; 279,45495–45502. 38. Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS.Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. JCell Biol. 2009; 186: 323–331. 39. Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T, Korsmeyer SJ. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science. 2003; 300,135–139. 40. Szegezdi E, Logue SE, Gorman AM, Samali A. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 2006; 7: 880–5. 41. Nakagawa, T, Yuan, J. Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J. Cell Biol. 2000; 150, 887-894. 42. Rao RV, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress to the cell death program.Cell Death and Differentiation. 2004; 11, 372–380. 43. Szegezdi E, Fitzgerald U, Samali A. Caspase-12 and ERstress-mediated apoptosis: the story so far. Ann N Y Acad Sci. 2003; 1010:186-94. 44. Chae HJ, Kim HR, Xu C, Bailly-Maitre B, Krajewska M, Krajewski S, Banares S,et al. BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Mol. Cell. 2004; 15,355–366. 45. Ishikawa T, Watanabe N, Nagano M, Kawai-Yamada M, Lam E. Bax inhibitor-1: a highly conserved endoplasmic reticulum-resident cell death suppressor. Cell Death Differ. 2011; 18,1271–1278. 46. Mei Y, Thompson MD, Cohen RA, Tong XY. Endoplasmic reticulum stress and related pathological processes. J Pharmacol Biomed Anal. 2013; 15;1(2):1000107.
  • Cheng EH, Wei MC, Weiler S, Flavell RA, WlindstenT, Korsmeyer SJ. BCL-2, BCL-X (L) sequester BH3 domainonly molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol. Cell. 2001; 8, 705–711. 48. Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta. 2013; 1833(12):3460-70. 49. Yorimitsu T, Klionsky DJ. Autophagy: molecular machinery for self-eating. Cell Death Differ. 2005; 12, 2:1542-52. 50. Bernales S, McDonald KL, Walter P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 2006; 4(12):e423. 51. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008; 451, 1069–1075. 52. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008; 132(1): 27–42. 53. Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T,et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell. Biol. 2006; 26,9220–9231. 54. Kouroku Y, Fujita E, Tanida I, Ueno T, Isoai A, Kumagai H, Ogawa S, et al. ER stress (PERK//eIF2[alpha] phosphorylation) mediates the polyglutamine induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ. 2007; 14(2):230–239. 55. Levine B, Yuan J. Autophagy in cell death: an innocent convict? Journal of Clinical Investigation. 2005; 115,2679– 2688. 56. Bernales S, Schuck S, Walter P. ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy. 2007; 3(3):285–287. 57. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009; 43:67–93. 58. Margariti A, Li H, Chen T, Martin D, Vizcay-Barrena G, Alam S, Karamariti E, Xiao Q, et al. XBP1 mRNA splicing triggers an autophagic response in endothelial cells through BECLIN-1 transcriptional activation. J.Biol.Chem. 2013; 288, 859–872. 59. Rubinstein AD, Eisenstein M, Ber Y, Bialik S, Kimchi A. The autophagy protein Atg12 associates with antiapoptotic Bcl-2 family members to promote mitochondrial apoptosis. Mol. Cell. 2011; 44,698–709
Year 2016, Volume: 6 Issue: 2, 0 - 0, 24.06.2016

Abstract

References

  • Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta. 2013; 1833(12):3460-70. 2. Ni M, Lee AS. ER chaperones in mammalian development and human diseases. FEBS Lett. 2007; 581(19):3641-51. 3. Zhang X, Xu C, Yu C, Chen W, Li Y. Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol. 2014; 21; 20(7): 17681776. 4. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nature, Molecular Cell Bıology. 2007; 8,519-529. 5. Bravo R, Parra V, Gatica D, Rodriguez AE, Torrealba N, Paredes F, Wang ZV, et al. Endoplasmic reticulum and the unfolded protein response: dynamics and metabolic integration. Int Rev Cell Mol Biol. 2013; 301:215-90. 6. Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat. Rev. Drug Discov. 2008; 7,1013–1030. 7. Kampinga HH, Craig EA. The HSP70 chaperone machinery: J proteins as drivers of functional specificity. Nat.Rev.Mol. CellBiol. 2010; 11, 579–592. 8. Appenzeller-Herzog C, Ellgaard L. The human PDI family: versatility packed into a single fold. Biochim.Biophys.Acta. 2008; 1783: 535–548. 9. Rutkevich LA, Williams DB. Participation of lectin chaperones and thiol oxido reductases in protein folding within the endoplasmic reticulum. Cell. Biol. 2011; 23,157– 166. 10. Bukau B, Weissman J, Horwich A. Molecular chaperones and protein quality control. Cell. 2006; 125, 443–451. 11. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell. 2010; 140:900–917. 12. Roussel BD, Kruppa AJ, Miranda E, Crowther DC, Lomas DA, Marciniak SJ. Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol. 2013; 12: 105–18. 13. Schröder M, Kaufman RJ. The mammalian unfolded protein response. Annual Review of Biochemistry. 2005; 74: 739–789. 14. Wang W, Groenendyk J, Michalak M. Endoplasmic reticulum stress associated responses in cancer. Biochimica et Biophysica. 2014; 1843(10):2143-9. 15. Wang S, Kaufman RJ. The impact of the unfolded protein response on human disease. J. Cell Biol. 2012; 197(7):85767. 16. Todd DJ, Lee AH, Glimcher LH. The endoplasmic reticulum stress response in immunity and autoimmunity. Nat Rev Immunol. 2008; 8(9):663-74. 17. Vincenz L, Jäger R, O'Dwyer M, Samali A. Endoplasmic reticulum stress and the unfolded protein response: targeting the Achilles heel of multiple myeloma. Mol Cancer Ther. 2013 Jun;12(6):831-43. 18. Kaufman RJ. Orchestrating the unfolded protein response in health and disease. J. Clin. Invest. 2002; 110: 1389–
  • 19. Maurel M, Chevet E. Endoplasmic reticulum stress signaling: the microRNA connection. Am J Physiol Cell Physiol. 2013; 304: C1117–C1126. 20. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003;11:619–633. 21. Hinnebusch AG, Natarajan K. Gcn4p, a master regulator of gene expression, is controlled at multiple levels by diverse signals of starvation and stress. Eukaryot. Cell. 2002; 1, 22–32. 22. Lu PD, Harding HP, Ron D. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. J. Cell Biol. 2004; 167, 27–33. 23. Vattem KM, Wek RC. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc. Natl. Acad. Sci. 2004; 101, 11269. 24. Cao SS, Kaufman RJ. Unfolded protein response. Current Biology. 2012; 22(16). 25. Verfaillie T, Salazar M, Velasco G, Agostinis P. Linking ER Stress to Autophagy: Potential Implications for Cancer Therapy. Int J Cell Biol. 2010;2010:930509. 26. Shamu CE, Walter P. Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J. 1996; 153028–3039. 27. Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2004; 11,381–389. 28. Hetz C, Martinon F, Rodriguez D, Glimcher LH.The unfolded protein response: integrating stress signals through the stress sensor IRE1↓. Physiol Rev. 2011; 91: 1219–1243. 29. Sidrauski C, and Walter P. The transmembrane kinase IRE1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell. 1997; 90,1031–1039. 30. Yoshida H, Haze K, Yanagi H, Yura T, Mori K. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors.The Journal of biological chemistry. 1998; 273:33741–33749. 31. Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS, Goldstein JL. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell. 2000; 6:1355–1364. 32. Haze K, Yoshida H, Yanagi H, Yura T, Mori K. Mol Biol Cell. 1999; 10:3787–3799. 33. Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R,Nagata K, Harding HP, Ron D. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes&development. 2004; 18:3066-3077. 34. Ron D, Hubbard SR. How IRE1 reacts to ER stress. Cell. 2008; 132, 24–26. 35. Deng X, Xiao L, Lang W, Gao F, Ruvolo P, May Jr. WS. Novel role for JNK as a stress-activated Bcl2 kinase. J. Biol. Chem. 2001; 276:23681–23688. 36. Lei K, Davis RJ. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc. Natl. Acad. Sci. 2003; 100,2432–2437. 37. Yamaguchi H, Wang HG. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J. Biol. Chem. 2004; 279,45495–45502. 38. Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS.Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. JCell Biol. 2009; 186: 323–331. 39. Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T, Korsmeyer SJ. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science. 2003; 300,135–139. 40. Szegezdi E, Logue SE, Gorman AM, Samali A. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 2006; 7: 880–5. 41. Nakagawa, T, Yuan, J. Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J. Cell Biol. 2000; 150, 887-894. 42. Rao RV, Ellerby HM, Bredesen DE. Coupling endoplasmic reticulum stress to the cell death program.Cell Death and Differentiation. 2004; 11, 372–380. 43. Szegezdi E, Fitzgerald U, Samali A. Caspase-12 and ERstress-mediated apoptosis: the story so far. Ann N Y Acad Sci. 2003; 1010:186-94. 44. Chae HJ, Kim HR, Xu C, Bailly-Maitre B, Krajewska M, Krajewski S, Banares S,et al. BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Mol. Cell. 2004; 15,355–366. 45. Ishikawa T, Watanabe N, Nagano M, Kawai-Yamada M, Lam E. Bax inhibitor-1: a highly conserved endoplasmic reticulum-resident cell death suppressor. Cell Death Differ. 2011; 18,1271–1278. 46. Mei Y, Thompson MD, Cohen RA, Tong XY. Endoplasmic reticulum stress and related pathological processes. J Pharmacol Biomed Anal. 2013; 15;1(2):1000107.
  • Cheng EH, Wei MC, Weiler S, Flavell RA, WlindstenT, Korsmeyer SJ. BCL-2, BCL-X (L) sequester BH3 domainonly molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol. Cell. 2001; 8, 705–711. 48. Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta. 2013; 1833(12):3460-70. 49. Yorimitsu T, Klionsky DJ. Autophagy: molecular machinery for self-eating. Cell Death Differ. 2005; 12, 2:1542-52. 50. Bernales S, McDonald KL, Walter P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 2006; 4(12):e423. 51. Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008; 451, 1069–1075. 52. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008; 132(1): 27–42. 53. Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T,et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell. Biol. 2006; 26,9220–9231. 54. Kouroku Y, Fujita E, Tanida I, Ueno T, Isoai A, Kumagai H, Ogawa S, et al. ER stress (PERK//eIF2[alpha] phosphorylation) mediates the polyglutamine induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ. 2007; 14(2):230–239. 55. Levine B, Yuan J. Autophagy in cell death: an innocent convict? Journal of Clinical Investigation. 2005; 115,2679– 2688. 56. Bernales S, Schuck S, Walter P. ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy. 2007; 3(3):285–287. 57. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009; 43:67–93. 58. Margariti A, Li H, Chen T, Martin D, Vizcay-Barrena G, Alam S, Karamariti E, Xiao Q, et al. XBP1 mRNA splicing triggers an autophagic response in endothelial cells through BECLIN-1 transcriptional activation. J.Biol.Chem. 2013; 288, 859–872. 59. Rubinstein AD, Eisenstein M, Ber Y, Bialik S, Kimchi A. The autophagy protein Atg12 associates with antiapoptotic Bcl-2 family members to promote mitochondrial apoptosis. Mol. Cell. 2011; 44,698–709
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Journal Section Articles
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Sümeyra Çetinkaya

Hatice Gül Dursun This is me

Publication Date June 24, 2016
Submission Date June 24, 2016
Published in Issue Year 2016 Volume: 6 Issue: 2

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AMA Çetinkaya S, Dursun HG. Endoplazmik Retikulum Stresinde Hücre Sağkalım ve Ölüm Kararı. Sakarya Tıp Dergisi. June 2016;6(2).

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