Hyperglycemia promotes p53-Mdm2 interaction but reduces p53 ubiquitination in RINm5F cells

The apoptosis of β cells induced by hyperglycemia has been associated with p53 mobilization to mitochondria and p53 phosphorylation. Murine double minute 2 (Mdm2) induces the degradation of p53 and thereby protects cells from apoptosis. We studied the effect of glucose at high concentration on the a...

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Veröffentlicht in:Molecular and cellular biochemistry 2015-07, Vol.405 (1-2), p.257-264
Hauptverfasser: Raúl, Barzalobre-Gerónimo, Antonio, Flores-López Luis, Arturo, Baiza-Gutman Luis, Miguel, Cruz, Rebeca, García-Macedo, Alejandro, Ávalos-Rodríguez, Alejandra, Contreras-Ramos, Margarita, Díaz-Flores, Clara, Ortega-Camarillo
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container_issue 1-2
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container_title Molecular and cellular biochemistry
container_volume 405
creator Raúl, Barzalobre-Gerónimo
Antonio, Flores-López Luis
Arturo, Baiza-Gutman Luis
Miguel, Cruz
Rebeca, García-Macedo
Alejandro, Ávalos-Rodríguez
Alejandra, Contreras-Ramos
Margarita, Díaz-Flores
Clara, Ortega-Camarillo
description The apoptosis of β cells induced by hyperglycemia has been associated with p53 mobilization to mitochondria and p53 phosphorylation. Murine double minute 2 (Mdm2) induces the degradation of p53 and thereby protects cells from apoptosis. We studied the effect of glucose at high concentration on the ability of Mdm2 to ubiquitinate p53 and promote its degradation. RINm5F cells were grown in RPMI-1640 medium with 5 or 30 mM glucose for varying periods of time. After this treatment, the expression of Mdm2 was measured using real-time PCR. The phosphorylation of Mdm2 at Ser166, p53 at Ser15, and the kinases Akt and ATM were measured by Western blotting. The formation of the p53-Mdm2 complex and p53 ubiquitination was assessed by p53 immunoprecipitation and immunofluorescence. Our results showed that high glucose reduced Mdm2 mRNA expression and protein concentration and increased Mdm2 and Akt phosphorylation, albeit with slower kinetics for Akt. It also promoted p53-Mdm2 complex formation, whereas p53 ubiquitination was suppressed. Furthermore, phosphorylation of both p53 Ser15 and ATM was increased in the presence of 30 mM glucose. These data indicate that high concentration glucose decrease the mRNA expression and cytosolic concentration of Mdm2. However, although the increase in glucose promoted the phosphorylation of Mdm2, it also decreased p53 ubiquitination, thus avoiding p53 degradation. In hyperglycemic conditions, such as diabetes mellitus, the reduction of pancreatic β cells mass is favored by stabilization of p53 in association with low p53 ubiquitination and reduced expression of Mdm2.
doi_str_mv 10.1007/s11010-015-2416-0
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Murine double minute 2 (Mdm2) induces the degradation of p53 and thereby protects cells from apoptosis. We studied the effect of glucose at high concentration on the ability of Mdm2 to ubiquitinate p53 and promote its degradation. RINm5F cells were grown in RPMI-1640 medium with 5 or 30 mM glucose for varying periods of time. After this treatment, the expression of Mdm2 was measured using real-time PCR. The phosphorylation of Mdm2 at Ser166, p53 at Ser15, and the kinases Akt and ATM were measured by Western blotting. The formation of the p53-Mdm2 complex and p53 ubiquitination was assessed by p53 immunoprecipitation and immunofluorescence. Our results showed that high glucose reduced Mdm2 mRNA expression and protein concentration and increased Mdm2 and Akt phosphorylation, albeit with slower kinetics for Akt. It also promoted p53-Mdm2 complex formation, whereas p53 ubiquitination was suppressed. Furthermore, phosphorylation of both p53 Ser15 and ATM was increased in the presence of 30 mM glucose. These data indicate that high concentration glucose decrease the mRNA expression and cytosolic concentration of Mdm2. However, although the increase in glucose promoted the phosphorylation of Mdm2, it also decreased p53 ubiquitination, thus avoiding p53 degradation. 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subjects Animals
Apoptosis
Apoptosis - physiology
Biochemistry
Biomedical and Life Sciences
Cardiology
Cell Line, Tumor
Glucose
Glucose - metabolism
Hyperglycemia
Hyperglycemia - metabolism
Insulin-Secreting Cells - metabolism
Insulin-Secreting Cells - physiology
Life Sciences
Medical Biochemistry
Mitochondria - metabolism
Mitochondria - physiology
Mitochondrial DNA
Oncology
Pancreatic beta cells
Phosphorylation - physiology
Phosphotransferases
Proto-Oncogene Proteins c-akt - metabolism
Proto-Oncogene Proteins c-mdm2 - metabolism
Rats
RNA
RNA, Messenger - genetics
Tumor proteins
Tumor Suppressor Protein p53 - metabolism
Ubiquitin
Ubiquitination - physiology
title Hyperglycemia promotes p53-Mdm2 interaction but reduces p53 ubiquitination in RINm5F cells
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