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Endocrine

, Volume 54, Issue 2, pp 383–395 | Cite as

Inhibition of tumor suppressor p53 preserves glycation-serum induced pancreatic beta-cell demise

  • Y. Li
  • T. Zhang
  • Q. Huang
  • Y. Sun
  • X. Chang
  • H. Zhang
  • Y. ZhuEmail author
  • X. HanEmail author
Original Article

Abstract

Tumor suppressor p53 is a transcriptional factor that determines cell fate in response to multiple stressors, such as oxidative stress and endoplasmic reticulum stress, in the majority of cells. However, its role in pancreatic beta cells is not well documented. Our previous research has revealed that glycation-serum (GS) induced pancreatic beta-cell demise through the AGEs-RAGE pathway. In the present study, we investigated the role of p53 in GS-related beta-cell demise. Using pancreatic islets beta-cell line INS-1 cells, we found that with GS treatment, the transcriptional activity of p53 was significantly evoked due to the increased amount of nuclear p53 protein. Resveratrol (RSV) was capable of further enhancing this transcriptional ability and consequently increased the population of dead beta cells under GS exposure. In contrast, inhibiting this transcriptional activity via p53 interference greatly protected beta cells from the damage provoked by GS, as well as damage strengthened by RSV. However, the pharmacological activation of PPARγ with troglitazone (TRO) only suppressed GS-induced, not RSV-induced, p53 activity. Moreover, the activation of PPARγ greatly preserved beta cells from GS-induced death. This protective effect recurred due to improved mitochondrial function with Bcl2 overexpression. Further, p53 activation could induce cellular apoptosis in primary rat islets. Our findings explore the broader role of p53 in regulating pancreatic beta-cell demise in the presence of GS and may provide a therapeutic target for the treatment and prevention of diabetes.

Keywords

p53 Glycation-serum Pancreatic beta-cell demise Diabetes 

Notes

Acknowledgments

This study was supported by research grants from (1) the National Natural Science Foundation of China (81420108007) and the National Basic Research Program of China (973 Program, 2012CB524903) to XH, (2) the National Natural Science Foundation of China (81200559) to YZ, and (3) the National Natural Science Foundation of China (81472989) to HZ. XH is a Fellow at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine.

Compliance with ethical standards

Conflict of interest

The authors took part in the conception and design of the study, as well as either drafting or critically revising the manuscript. The authors have approved the final version of the manuscript.

Supplementary material

12020_2016_979_MOESM1_ESM.doc (38 kb)
Supplementary material 1 (DOC 39 kb)
12020_2016_979_MOESM2_ESM.tif (345 kb)
Supplemental Figure 1 Analysis of transcriptional activities with GS treatment. INS-1 cells were co-transfected with Myc-luc, ARE-luc, Rb-luc, AP-1-luc, NF-κB-luc and pRL-CMV (10:1) constructs for 24 h, followed by treatment with NG or 10 % GS for a further 24 h. Lysates were harvested for the dual-luciferase reporter assay. The firefly luciferase activity representing report genes activity was normalized to the Renilla activity. The data represent three separate experiments. **p<0.01 versus NG (TIFF 346 kb)
12020_2016_979_MOESM3_ESM.tif (2.8 mb)
Supplemental Figure 2 p53 binding specificity examination. INS-1 cells were in the presence of NG or 10 % GS for 2 h, and then, nuclear proteins were extracted for EMSA assay. (a) Unlabeled p53 probe was used to identify the binding specificity. (b) An anti-p53 antibody was used to identify the binding specificity (TIFF 2822 kb)
12020_2016_979_MOESM4_ESM.tif (3.4 mb)
Supplementary material 4 (TIFF 3468 kb)
12020_2016_979_MOESM5_ESM.tif (2.1 mb)
Supplementary material 5 (TIFF 2133 kb)

References

  1. 1.
    Z. Fu, E.R. Gilbert, D. Liu, Regulation of insulin synthesis and secretion and pancreatic beta-cell dysfunction in diabetes. Curr. Diabetes Rev. 9, 25–53 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    S. Cernea, M. Dobreanu, Diabetes and beta cell function: from mechanisms to evaluation and clinical implications. Biochemia Medica 23, 266–280 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Y. Hirasawa, Y. Matsui, S. Ohtsu, K. Yamane, T. Toyoshi, K. Kyuki, T. Sakai, Y. Feng, T. Nagamatsu, Involvement of hyperglycemia in deposition of aggregated protein in glomeruli of diabetic mice. Eur. J. Pharmacol. 601, 129–135 (2008)CrossRefPubMedGoogle Scholar
  4. 4.
    K. Nowotny, T. Jung, A. Hohn, D. Weber, T. Grune, Advanced glycation end products and oxidative stress in type 2 diabetes mellitus. Biomolecules 5, 194–222 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    J. O’Brien, P.A. Morrissey, Nutritional and toxicological aspects of the Maillard browning reaction in foods. Crit. Rev. Food Sci. Nutr. 28, 211–248 (1989)CrossRefPubMedGoogle Scholar
  6. 6.
    R. Ramasamy, S.J. Vannucci, S.S. Yan, K. Herold, S.F. Yan, A.M. Schmidt, Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology 15, 16R–28R (2005)CrossRefPubMedGoogle Scholar
  7. 7.
    H. Vlassara, G.E. Striker, Advanced glycation end products in diabetes and diabetic complications. Endocrinol. Metab. Clin. N. Am. 42, 697–719 (2013)CrossRefGoogle Scholar
  8. 8.
    R. Pokupec, M. Kalauz, N. Turk, Z. Turk, Advanced glycation end products in human diabetic and non-diabetic cataractous lenses. Graefes. Arch. Clin. Exp. Ophthalmol. 241, 378–384 (2003)CrossRefPubMedGoogle Scholar
  9. 9.
    O. Sandu, K. Song, W. Cai, F. Zheng, J. Uribarri, H. Vlassara, Insulin resistance and type 2 diabetes in high-fat-fed mice are linked to high glycotoxin intake. Diabetes 54, 2314–2319 (2005)CrossRefPubMedGoogle Scholar
  10. 10.
    E.J. Gallagher, D. LeRoith, E. Karnieli, The metabolic syndrome-from insulin resistance to obesity and diabetes. Endocrinol. Metab. Clin. N. Am. 37, 559–579 (2008)CrossRefGoogle Scholar
  11. 11.
    W. Cai, M. Ramdas, L. Zhu, X. Chen, G.E. Striker, H. Vlassara, Oral advanced glycation end products (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1. Proc. Natl. Acad. Sci. USA 109, 15888–15893 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    G. Luciano Viviani, A. Puddu, G. Sacchi, A. Garuti, D. Storace, A. Durante, F. Monacelli, P. Odetti, Glycated fetal calf serum affects the viability of an insulin-secreting cell line in vitro. Metabolism. 57, 163–169 (2008)CrossRefPubMedGoogle Scholar
  13. 13.
    X. Kong, G.D. Wang, M.Z. Ma, R.Y. Deng, L.Q. Guo, J.X. Zhang, J.R. Yang, Q. Su, Sesamin ameliorates advanced glycation end products-induced pancreatic beta-cell dysfunction and apoptosis. Nutrients 7, 4689–4704 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    J. Uribarri, W. Cai, M. Ramdas, S. Goodman, R. Pyzik, X. Chen, L. Zhu, G.E. Striker, H. Vlassara, Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Diabetes Care 34, 1610–1616 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    H. Vlassara, G.E. Striker, AGE restriction in diabetes mellitus: a paradigm shift. Nat. Rev. Endocrinol. 7, 526–539 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    C. Luevano-Contreras, M.E. Garay-Sevilla, K. Wrobel, J.M. Malacara, K. Wrobel, Dietary advanced glycation end products restriction diminishes inflammation markers and oxidative stress in patients with type 2 diabetes mellitus. J. Clin. Biochem. Nutr. 52, 22–26 (2013)CrossRefPubMedGoogle Scholar
  17. 17.
    A. Puddu, R. Sanguineti, A. Durante, A. Nencioni, F. Mach, F. Montecucco, G.L. Viviani, Glucagon-like peptide-1 triggers protective pathways in pancreatic beta-cells exposed to glycated serum. Mediat. Inflamm. 2013, 317120 (2013)Google Scholar
  18. 18.
    T. Shu, Y. Zhu, H. Wang, Y. Lin, Z. Ma, X. Han, AGEs decrease insulin synthesis in pancreatic beta-cell by repressing Pdx-1 protein expression at the post-translational level. PLoS ONE 6, e18782 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Y. Zhu, T. Shu, Y. Lin, H. Wang, J. Yang, Y. Shi, X. Han, Inhibition of the receptor for advanced glycation end products (RAGE) protects pancreatic beta-cells. Biochem. Biophys. Res. Commun. 404, 159–165 (2011)CrossRefPubMedGoogle Scholar
  20. 20.
    L. Jiang, J.H. Hickman, S.J. Wang, W. Gu, Dynamic roles of p53-mediated metabolic activities in ROS-induced stress responses. Cell Cycle 14, 2881–2885 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    N. Sen, Y.K. Satija, S. Das, PGC-1alpha, a key modulator of p53, promotes cell survival upon metabolic stress. Mol. Cell 44, 621–634 (2011)CrossRefPubMedGoogle Scholar
  22. 22.
    S.E. Thomas, E. Malzer, A. Ordonez, L.E. Dalton, E.F. van ‘t Wout, E. Liniker, D.C. Crowther, D.A. Lomas, S.J. Marciniak, p53 and translation attenuation regulate distinct cell cycle checkpoints during endoplasmic reticulum (ER) stress. J. Biol. Chem. 288, 7606–7617 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    M. Oren, Decision making by p53: life, death and cancer. Cell Death Differ. 10, 431–442 (2003)CrossRefPubMedGoogle Scholar
  24. 24.
    Z. Li, M. Ni, J. Li, Y. Zhang, Q. Ouyang, C. Tang, Decision making of the p53 network: death by integration. J. Theor. Biol. 271, 205–211 (2011)CrossRefPubMedGoogle Scholar
  25. 25.
    S. Zhang, J. Liu, E.L. Saafi, G.J. Cooper, Induction of apoptosis by human amylin in RINm5F islet beta-cells is associated with enhanced expression of p53 and p21WAF1/CIP1. FEBS Lett. 455, 315–320 (1999)CrossRefPubMedGoogle Scholar
  26. 26.
    P. Lovis, E. Roggli, D.R. Laybutt, S. Gattesco, J.Y. Yang, C. Widmann, A. Abderrahmani, R. Regazzi, Alterations in microRNA expression contribute to fatty acid-induced pancreatic beta-cell dysfunction. Diabetes 57, 2728–2736 (2008)CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    H. Yuan, X. Zhang, X. Huang, Y. Lu, W. Tang, Y. Man, S. Wang, J. Xi, J. Li, NADPH oxidase 2-derived reactive oxygen species mediate FFAs-induced dysfunction and apoptosis of beta-cells via JNK, p38 MAPK and p53 pathways. PLoS ONE 5, e15726 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    V.B. Cismasiu, J. Duque, E. Paskaleva, D. Califano, S. Ghanta, H.A. Young, D. Avram, BCL11B enhances TCR/CD28-triggered NF-kappaB activation through up-regulation of Cot kinase gene expression in T-lymphocytes. Biochem. J. 417, 457–466 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Y. Lin, X. Tang, Y. Zhu, T. Shu, X. Han, Identification of PARP-1 as one of the transcription factors binding to the repressor element in the promoter region of COX-2. Arch. Biochem. Biophys. 505, 123–129 (2011)CrossRefPubMedGoogle Scholar
  30. 30.
    S.D. Varma, P.S. Devamanoharan, A.H. Ali, Formation of advanced glycation end (AGE) products in diabetes: prevention by pyruvate and alpha-ketoglutarate. Mol. Cell. Biochem. 171, 23–28 (1997)CrossRefPubMedGoogle Scholar
  31. 31.
    L.B. Lingelbach, A.E. Mitchell, R.B. Rucker, R.B. McDonald, Accumulation of advanced glycation end products in aging male Fischer 344 rats during long-term feeding of various dietary carbohydrates. J. Nutr. 130, 1247–1255 (2000)PubMedGoogle Scholar
  32. 32.
    Z. Zhao, C. Zhao, X.H. Zhang, F. Zheng, W. Cai, H. Vlassara, Z.A. Ma, Advanced glycation end products inhibit glucose-stimulated insulin secretion through nitric oxide-dependent inhibition of cytochrome c oxidase and adenosine triphosphate synthesis. Endocrinology 150, 2569–2576 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    M.T. Coughlan, F.Y. Yap, D.C. Tong, S. Andrikopoulos, A. Gasser, V. Thallas-Bonke, D.E. Webster, J. Miyazaki, T.W. Kay, R.M. Slattery, D.M. Kaye, B.G. Drew, B.A. Kingwell, S. Fourlanos, P.H. Groop, L.C. Harrison, M. Knip, J.M. Forbes, Advanced glycation end products are direct modulators of beta-cell function. Diabetes 60, 2523–2532 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Y. Zhu, A. Ma, H. Zhang, C. Li, PPARgamma activation attenuates glycated-serum induced pancreatic beta-cell dysfunction through enhancing Pdx1 and Mafa protein stability. PLoS ONE 8, e56386 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ge QM, Dong Y, Su Q. Effects of glucose and advanced glycation end products on oxidative stress in MIN6 cells. Cell Mol Biol (Noisy-le-grand). 2010; 56 Suppl: OL1231-8Google Scholar
  36. 36.
    A.K. Mohamed, A. Bierhaus, S. Schiekofer, H. Tritschler, R. Ziegler, P.P. Nawroth, The role of oxidative stress and NF-kappaB activation in late diabetic complications. Biofactors 10, 157–167 (1999)CrossRefPubMedGoogle Scholar
  37. 37.
    K.C. Lan, C.Y. Chiu, C.W. Kao, K.H. Huang, C.C. Wang, K.T. Huang, K.S. Tsai, M.L. Sheu, S.H. Liu, Advanced glycation end-products induce apoptosis in pancreatic islet endothelial cells via NF-kappaB-activated cyclooxygenase-2/prostaglandin E2 up-regulation. PLoS ONE 10, e0124418 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    D. Melloul, Role of NF-kappaB in beta-cell death. Biochem. Soc. Trans. 36, 334–339 (2008)CrossRefPubMedGoogle Scholar
  39. 39.
    C. Arous, P.G. Ferreira, E.T. Dermitzakis, P.A. Halban, Short term exposure of beta cells to low concentrations of interleukin-1beta improves insulin secretion through focal adhesion and actin remodeling and regulation of gene expression. J. Biol. Chem. 290, 6653–6669 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    M. Cnop, N. Welsh, J.C. Jonas, A. Jorns, S. Lenzen, D.L. Eizirik, Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(Suppl 2), S97–S107 (2005)CrossRefPubMedGoogle Scholar
  41. 41.
    M.Y. Donath, J. Storling, K. Maedler, T. Mandrup-Poulsen, Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes. J. Mol. Med. 81, 455–470 (2003)CrossRefPubMedGoogle Scholar
  42. 42.
    I. Rakatzi, H. Mueller, O. Ritzeler, N. Tennagels, J. Eckel, Adiponectin counteracts cytokine- and fatty acid-induced apoptosis in the pancreatic beta-cell line INS-1. Diabetologia 47, 249–258 (2004)CrossRefPubMedGoogle Scholar
  43. 43.
    K. Maedler, P. Sergeev, F. Ris, J. Oberholzer, H.I. Joller-Jemelka, G.A. Spinas, N. Kaiser, P.A. Halban, M.Y. Donath, Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest. 110, 851–860 (2002)CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    I. Kharroubi, L. Ladriere, A.K. Cardozo, Z. Dogusan, M. Cnop, D.L. Eizirik, Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology 145, 5087–5096 (2004)CrossRefPubMedGoogle Scholar
  45. 45.
    J. Buteau, W. El-Assaad, C.J. Rhodes, L. Rosenberg, E. Joly, M. Prentki, Glucagon-like peptide-1 prevents beta cell glucolipotoxicity. Diabetologia 47, 806–815 (2004)CrossRefPubMedGoogle Scholar
  46. 46.
    F. Xin, L. Jiang, X. Liu, C. Geng, W. Wang, L. Zhong, G. Yang, M. Chen, Bisphenol A induces oxidative stress-associated DNA damage in INS-1 cells. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 769, 29–33 (2014)CrossRefPubMedGoogle Scholar
  47. 47.
    S. Tornovsky-Babeay, D. Dadon, O. Ziv, E. Tzipilevich, T. Kadosh, R. Schyr-Ben Haroush, A. Hija, M. Stolovich-Rain, J. Furth-Lavi, Z. Granot, S. Porat, L.H. Philipson, K.C. Herold, T.R. Bhatti, C. Stanley, F.M. Ashcroft, P. In’t Veld, A. Saada, M.A. Magnuson, B. Glaser, Y. Dor, Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in beta cells. Cell Metab. 19, 109–121 (2014)CrossRefPubMedGoogle Scholar
  48. 48.
    D.A. Cunha, M. Igoillo-Esteve, E.N. Gurzov, C.M. Germano, N. Naamane, I. Marhfour, M. Fukaya, J.M. Vanderwinden, C. Gysemans, C. Mathieu, L. Marselli, P. Marchetti, H.P. Harding, D. Ron, D.L. Eizirik, M. Cnop, Death protein 5 and p53-upregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human beta-cell apoptosis. Diabetes 61, 2763–2775 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    O.D. Maddocks, C.R. Berkers, S.M. Mason, L. Zheng, K. Blyth, E. Gottlieb, K.H. Vousden, Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493, 542–546 (2013)CrossRefPubMedGoogle Scholar
  50. 50.
    C. Evans-Molina, R.D. Robbins, T. Kono, S.A. Tersey, G.L. Vestermark, C.S. Nunemaker, J.C. Garmey, T.G. Deering, S.R. Keller, B. Maier, R.G. Mirmira, Peroxisome proliferator-activated receptor gamma activation restores islet function in diabetic mice through reduction of endoplasmic reticulum stress and maintenance of euchromatin structure. Mol. Cell. Biol. 29, 2053–2067 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    K.K. Brown, B.R. Henke, S.G. Blanchard, J.E. Cobb, R. Mook, I. Kaldor, S.A. Kliewer, J.M. Lehmann, J.M. Lenhard, W.W. Harrington, P.J. Novak, W. Faison, J.G. Binz, M.A. Hashim, W.O. Oliver, H.R. Brown, D.J. Parks, K.D. Plunket, W.Q. Tong, J.A. Menius, K. Adkison, S.A. Noble, T.M. Willson, A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat. Diabetes 48, 1415–1424 (1999)CrossRefPubMedGoogle Scholar
  52. 52.
    J.S. Wu, T.N. Lin, K.K. Wu, Rosiglitazone and PPAR-gamma overexpression protect mitochondrial membrane potential and prevent apoptosis by upregulating anti-apoptotic Bcl-2 family proteins. J. Cell. Physiol. 220, 58–71 (2009)CrossRefPubMedGoogle Scholar
  53. 53.
    Y. Ren, C. Sun, Y. Sun, H. Tan, Y. Wu, B. Cui, Z. Wu, PPAR gamma protects cardiomyocytes against oxidative stress and apoptosis via Bcl-2 upregulation. Vascul. Pharmacol. 51, 169–174 (2009)CrossRefPubMedGoogle Scholar
  54. 54.
    J.C. Strum, R. Shehee, D. Virley, J. Richardson, M. Mattie, P. Selley, S. Ghosh, C. Nock, A. Saunders, A. Roses, Rosiglitazone induces mitochondrial biogenesis in mouse brain. J. Alzheimers Dis. 11, 45–51 (2007)PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes CenterNanjing Medical UniversityNanjingChina
  2. 2.Department of Obstetrics and GynecologyFirst Affiliated Hospital of Nanjing Medical UniversityNanjingChina

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