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

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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.

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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.

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Authors and Affiliations

  1. Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, 210029, Jiangsu, China

    Y. Li, T. Zhang, Q. Huang, Y. Sun, X. Chang, Y. Zhu & X. Han

  2. Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    H. Zhang

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  1. Y. Li
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Supplementary material 1 (DOC 39 kb)

12020_2016_979_MOESM2_ESM.tif

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

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)

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Li, Y., Zhang, T., Huang, Q. et al. Inhibition of tumor suppressor p53 preserves glycation-serum induced pancreatic beta-cell demise. Endocrine 54, 383–395 (2016). https://doi.org/10.1007/s12020-016-0979-5

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