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Effect of High-Glucose Concentration on the E3 Ubiquitin Ligase Activity of Mdm2

  1. RAUL BARZALOBRE GERONIMO
  1. Mexico City, Mexico
Diabetes 2018 Jul; 67(Supplement 1): -. https://doi.org/10.2337/db18-2465-PUB
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Abstract

The degradation of p53 occurs via ubiquitin-26S proteosome, after Mdm2 (murine double minute 2) marks p53 with ubiquitins. The concentration and phosphorylation of Mdm2 and p53, greatly affect the ubiquitination rate of p53, by avoiding the recognition and physical interaction between p53 and Mdm2. Phosphorylation of Mdm2 in Ser395 by ATM decreases its ability to direct the degradation of p53. Therefore, we aim to study the effects of high glucose concentrations on the RING domain of Mdm2 and its ubiquitin E3 ligase activity.

We cultured RINm5F cells in RPMI-1640 medium supplemented with 10% fetal bovine serum (v / v) at two concentrations of glucose 5 and 30 mM for up to 72 h, in a humid atmosphere at 37 ° C and 5% CO2. At the end of the treatment the cells were lysed to separate the nuclear and cytosolic fraction. After quantifying the proteins, they were visualized on SDS-PAGE and transferred to a PVDF membrane. Primary antibodies against Mdm2, Mdm2 p-Ser395, ATM, Arf, c-Abl, and ubiquitin were used and revealed using an amplified fluorescence kit from GE.

The results show that the stress caused by high concentrations of glucose stimulates the phosphorylation of Mdm2 in Ser 395 by ATM activation. The phosphorylation of Ser395 alters the RING domain of Mdm2 and decreases its ubiquitin E3 ligase activity, ubiquitination and degradation of p53. Therefore, stress due to increased glucose decreases the ubiquitin E3 ligase activity of Mdm2 by inducing the phosphorylation of this residue, which leads to the stabilization and increase of p53 and the subsequent activation of apoptotic events.

The Ser 395 residue of the RING domain is important for the efficient function of ubiquitin ligase of Mdm2 in β cells under conditions of hyperglycemia.

Disclosure R. Barzalobre Geronimo: None.

  • © 2018 by the American Diabetes Association.
http://www.diabetesjournals.org/content/license

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

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Effect of High-Glucose Concentration on the E3 Ubiquitin Ligase Activity of Mdm2
RAUL BARZALOBRE GERONIMO
Diabetes Jul 2018, 67 (Supplement 1) 2465-PUB; DOI: 10.2337/db18-2465-PUB

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Effect of High-Glucose Concentration on the E3 Ubiquitin Ligase Activity of Mdm2
RAUL BARZALOBRE GERONIMO
Diabetes Jul 2018, 67 (Supplement 1) 2465-PUB; DOI: 10.2337/db18-2465-PUB
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