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.

Glucolipotoxicity-Inhibited miR-299-5p Regulates Pancreatic β-Cell Function and Survival

“…The mouse pancreatic b-cell lines MIN6 and b-TC-6 (passage [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] were grown in DMEM (Invitrogen, Grand Island, NY) containing 15% FBS (Gibco, Burlington, Ontario, Canada). The rat pancreatic b-cell line INS-1 (passage 16-30) was cultured in RPMI medium (Invitrogen) containing 10% FBS.…”

“…TUNEL staining was performed using the In Situ Cell Apoptosis Detection Kit III (fluorescein isothiocyanate) (Boster Biological Technology, Wuhan, Hubei, China), according to the manufacturer's protocol (22). Islets and MIN6 cells were observed under laser scanning confocal microscope (FV1200; Olympus, Tokyo, Japan).…”

Is p53 Involved in Tissue‐Specific Insulin Resistance Formation?

“…An elevated level of AGEs is one of the most vivid signs of chronic hyperglycemia, supporting pathogenesis of diabetic complications [ 164 ]. p53 was also found critical for apoptosis of β cells in a glycation-serum-induced mechanism [ 165 ]. Studies performed on INS-1 cells and primary rat islets indicated that transcriptional activity of p53 becomes substantially increased in the presence of glycation serum (GS) and contributes to cell apoptosis.…”

ATM and P53 differentially regulate pancreatic beta cell survival in Ins1E cells

“…Since some monogenetic forms of diabetes such as MODY4 also appear to involve apoptotic processes mediated by P53 target genes [83], analyses of DDR activation in MODY patient samples or animal models could further help to understand these rare diseases. In addition, P53 has also been linked to beta cell apoptosis induced by additional mechanisms including hyperglycemia [84] as well as advanced glycation end products [85], and it appears worthwhile to analyze the impact of ATM under these conditions. As a general limitation of our study, our findings are based on acute genetic and pharmacological (but not Cre/loxP or CrispR/Cas9 mediated) manipulation of an immortal rat beta cell line, which shows lower inducibility of glucose stimulated insulin secretion compared to primary beta cells, likely as a compensation for its very high proliferation rate [86].…”