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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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. 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.</description><identifier>ISSN: 0300-8177</identifier><identifier>EISSN: 1573-4919</identifier><identifier>DOI: 10.1007/s11010-015-2416-0</identifier><identifier>PMID: 25912675</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>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</subject><ispartof>Molecular and cellular biochemistry, 2015-07, Vol.405 (1-2), p.257-264</ispartof><rights>Springer Science+Business Media New York 2015</rights><rights>COPYRIGHT 2015 Springer</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c542t-5219cfbd7bd9461ee491b914cfcdad2385ce70237162e88a96b3b522a10719233</citedby><cites>FETCH-LOGICAL-c542t-5219cfbd7bd9461ee491b914cfcdad2385ce70237162e88a96b3b522a10719233</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11010-015-2416-0$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11010-015-2416-0$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25912675$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Raúl, Barzalobre-Gerónimo</creatorcontrib><creatorcontrib>Antonio, Flores-López Luis</creatorcontrib><creatorcontrib>Arturo, Baiza-Gutman Luis</creatorcontrib><creatorcontrib>Miguel, Cruz</creatorcontrib><creatorcontrib>Rebeca, García-Macedo</creatorcontrib><creatorcontrib>Alejandro, Ávalos-Rodríguez</creatorcontrib><creatorcontrib>Alejandra, Contreras-Ramos</creatorcontrib><creatorcontrib>Margarita, Díaz-Flores</creatorcontrib><creatorcontrib>Clara, Ortega-Camarillo</creatorcontrib><title>Hyperglycemia promotes p53-Mdm2 interaction but reduces p53 ubiquitination in RINm5F cells</title><title>Molecular and cellular biochemistry</title><addtitle>Mol Cell Biochem</addtitle><addtitle>Mol Cell Biochem</addtitle><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.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - physiology</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cardiology</subject><subject>Cell Line, Tumor</subject><subject>Glucose</subject><subject>Glucose - metabolism</subject><subject>Hyperglycemia</subject><subject>Hyperglycemia - metabolism</subject><subject>Insulin-Secreting Cells - metabolism</subject><subject>Insulin-Secreting Cells - physiology</subject><subject>Life Sciences</subject><subject>Medical Biochemistry</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondria - physiology</subject><subject>Mitochondrial DNA</subject><subject>Oncology</subject><subject>Pancreatic beta cells</subject><subject>Phosphorylation - physiology</subject><subject>Phosphotransferases</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Proto-Oncogene Proteins c-mdm2 - metabolism</subject><subject>Rats</subject><subject>RNA</subject><subject>RNA, Messenger - genetics</subject><subject>Tumor proteins</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Ubiquitin</subject><subject>Ubiquitination - physiology</subject><issn>0300-8177</issn><issn>1573-4919</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqFkU2L1TAUhoMoznX0B7iRghs3Gc_JR9Msh8FxBkYF0Y2bkKbpJUOb3knaxf33pnb8RJEQAjnPe3jPeQl5jnCGAOp1RgQECigpE1hTeEB2KBWnQqN-SHbAAWiDSp2QJznfQoEB8TE5YVIjq5XckS9Xx4NP--Ho_BhsdUjTOM0-VwfJ6btuZFWIs0_WzWGKVbvMVfLd4jagWtpwt4Q5RPutHGL18fr9KC8r54chPyWPejtk_-z-PSWfL998uriiNx_eXl-c31AnBZupZKhd33aq7bSo0ftivtUoXO862zHeSOcVMK6wZr5prK5b3krGLIJCzTg_Ja-2vsX83eLzbMaQVwc2-mnJBhXocqUS_0frRgjOQLKCvvwDvZ2WFMsghdKagVBa_aT2dvAmxH6ay7LWpuZccFnMMw6FOvsLVU5Xlu6m6PtQ_n8T4CZwaco5-d4cUhhtOhoEs0ZvtuhNid6s0ZtV8-Le8NKOvvuh-J51AdgG5FKKe59-meifXb8CQhS0oQ</recordid><startdate>20150701</startdate><enddate>20150701</enddate><creator>Raúl, Barzalobre-Gerónimo</creator><creator>Antonio, Flores-López Luis</creator><creator>Arturo, Baiza-Gutman Luis</creator><creator>Miguel, Cruz</creator><creator>Rebeca, García-Macedo</creator><creator>Alejandro, Ávalos-Rodríguez</creator><creator>Alejandra, Contreras-Ramos</creator><creator>Margarita, Díaz-Flores</creator><creator>Clara, Ortega-Camarillo</creator><general>Springer US</general><general>Springer</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20150701</creationdate><title>Hyperglycemia promotes p53-Mdm2 interaction but reduces p53 ubiquitination in RINm5F cells</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c542t-5219cfbd7bd9461ee491b914cfcdad2385ce70237162e88a96b3b522a10719233</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - physiology</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Cardiology</topic><topic>Cell Line, Tumor</topic><topic>Glucose</topic><topic>Glucose - metabolism</topic><topic>Hyperglycemia</topic><topic>Hyperglycemia - metabolism</topic><topic>Insulin-Secreting Cells - metabolism</topic><topic>Insulin-Secreting Cells - physiology</topic><topic>Life Sciences</topic><topic>Medical Biochemistry</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondria - physiology</topic><topic>Mitochondrial DNA</topic><topic>Oncology</topic><topic>Pancreatic beta cells</topic><topic>Phosphorylation - physiology</topic><topic>Phosphotransferases</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Proto-Oncogene Proteins c-mdm2 - metabolism</topic><topic>Rats</topic><topic>RNA</topic><topic>RNA, Messenger - genetics</topic><topic>Tumor proteins</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Ubiquitin</topic><topic>Ubiquitination - 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Academic</collection><jtitle>Molecular and cellular biochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Raúl, Barzalobre-Gerónimo</au><au>Antonio, Flores-López Luis</au><au>Arturo, Baiza-Gutman Luis</au><au>Miguel, Cruz</au><au>Rebeca, García-Macedo</au><au>Alejandro, Ávalos-Rodríguez</au><au>Alejandra, Contreras-Ramos</au><au>Margarita, Díaz-Flores</au><au>Clara, Ortega-Camarillo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hyperglycemia promotes p53-Mdm2 interaction but reduces p53 ubiquitination in RINm5F cells</atitle><jtitle>Molecular and cellular biochemistry</jtitle><stitle>Mol Cell Biochem</stitle><addtitle>Mol Cell Biochem</addtitle><date>2015-07-01</date><risdate>2015</risdate><volume>405</volume><issue>1-2</issue><spage>257</spage><epage>264</epage><pages>257-264</pages><issn>0300-8177</issn><eissn>1573-4919</eissn><abstract>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.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>25912675</pmid><doi>10.1007/s11010-015-2416-0</doi><tpages>8</tpages></addata></record> |
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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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