title: Inhibition of tumor suppressor p53 preserves glycation-serum induced pancreatic beta-cell demise.
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.
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
authors.forename: T
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
authors.forename: X
authors.initials: X
authors.lastname: Chang
authors.affiliation: Department of Obstetrics and Gynecology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, 210029, Jiangsu, China. zhuyx@njmu.edu.cn.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, 210029, Jiangsu, China. hanxiao@njmu.edu.cn.
authors.forename: X
authors.initials: X
authors.lastname: Han
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002839:Chromans / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*; D000077288:Troglitazone; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; C000617196:Bcl2 protein, rat; D002839:Chromans; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D020011:Protective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D013267:Stilbenes; D045162:Thiazolidinediones; D016159:Tumor Suppressor Protein p53; D000077288:Troglitazone; D000077185:Resveratrol
keywords: Diabetes; Glycation-serum; Pancreatic beta-cell demise; p53