Ubiquitination and degradation of ribonucleotide reductase M1 by the polycomb group proteins RNF2 and Bmi1 and cellular response to gemcitabine.

Ribonucleotide reductase M1 (RRM1) is required for mammalian deoxyribonucleotide (dNTP) metabolism. It is the primary target of the antimetabolite drug gemcitabine, which is among the most efficacious and most widely used cancer therapeutics. Gemcitabine directly binds to RRM1 and irreversibly inact...

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Autores principales: Yingtao Zhang, Xin Li, Zhengming Chen, Gerold Bepler
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Publicado: Public Library of Science (PLoS) 2014
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spelling oai:doaj.org-article:baf60fec75ac48fea5e00121a55b48792021-11-18T08:28:58ZUbiquitination and degradation of ribonucleotide reductase M1 by the polycomb group proteins RNF2 and Bmi1 and cellular response to gemcitabine.1932-620310.1371/journal.pone.0091186https://doaj.org/article/baf60fec75ac48fea5e00121a55b48792014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24614341/?tool=EBIhttps://doaj.org/toc/1932-6203Ribonucleotide reductase M1 (RRM1) is required for mammalian deoxyribonucleotide (dNTP) metabolism. It is the primary target of the antimetabolite drug gemcitabine, which is among the most efficacious and most widely used cancer therapeutics. Gemcitabine directly binds to RRM1 and irreversibly inactivates ribonucleotide reductase. Intra-tumoral RRM1 levels are predictive of gemcitabine's therapeutic efficacy. The mechanisms that regulate intracellular RRM1 levels are largely unknown. Here, we identified the E3 ubiquitin-protein ligases RNF2 and Bmi1 to associate with RRM1 with subsequent poly-ubiquitination at either position 48 or 63 of ubiquitin. The lysine residues 224 and 548 of RRM1 were identified as major ubiquitination sites. We show that ubiquitinated RRM1 undergoes proteasome-mediated degradation and that targeted post-transcriptional silencing of RNF2 and Bmi1 results in increased RRM1 levels and resistance to gemcitabine. Immunohistochemical analyses of 187 early-stage lung cancer tumor specimens revealed a statistically significant co-expression of RRM1 and Bmi1. We were unable to identify suitable reagents for in situ quantification of RNF2. Our findings suggest that Bmi1 and possibly RNF2 may be attractive biomarkers of gemcitabine resistance in the context of RRM1 expression. They also provide novel information for the rational design of gemcitabine-proteasome inhibitor combination therapies, which so far have been unsuccessful if given to patients without taking the molecular context into account.Yingtao ZhangXin LiZhengming ChenGerold BeplerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 3, p e91186 (2014)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Yingtao Zhang
Xin Li
Zhengming Chen
Gerold Bepler
Ubiquitination and degradation of ribonucleotide reductase M1 by the polycomb group proteins RNF2 and Bmi1 and cellular response to gemcitabine.
description Ribonucleotide reductase M1 (RRM1) is required for mammalian deoxyribonucleotide (dNTP) metabolism. It is the primary target of the antimetabolite drug gemcitabine, which is among the most efficacious and most widely used cancer therapeutics. Gemcitabine directly binds to RRM1 and irreversibly inactivates ribonucleotide reductase. Intra-tumoral RRM1 levels are predictive of gemcitabine's therapeutic efficacy. The mechanisms that regulate intracellular RRM1 levels are largely unknown. Here, we identified the E3 ubiquitin-protein ligases RNF2 and Bmi1 to associate with RRM1 with subsequent poly-ubiquitination at either position 48 or 63 of ubiquitin. The lysine residues 224 and 548 of RRM1 were identified as major ubiquitination sites. We show that ubiquitinated RRM1 undergoes proteasome-mediated degradation and that targeted post-transcriptional silencing of RNF2 and Bmi1 results in increased RRM1 levels and resistance to gemcitabine. Immunohistochemical analyses of 187 early-stage lung cancer tumor specimens revealed a statistically significant co-expression of RRM1 and Bmi1. We were unable to identify suitable reagents for in situ quantification of RNF2. Our findings suggest that Bmi1 and possibly RNF2 may be attractive biomarkers of gemcitabine resistance in the context of RRM1 expression. They also provide novel information for the rational design of gemcitabine-proteasome inhibitor combination therapies, which so far have been unsuccessful if given to patients without taking the molecular context into account.
format article
author Yingtao Zhang
Xin Li
Zhengming Chen
Gerold Bepler
author_facet Yingtao Zhang
Xin Li
Zhengming Chen
Gerold Bepler
author_sort Yingtao Zhang
title Ubiquitination and degradation of ribonucleotide reductase M1 by the polycomb group proteins RNF2 and Bmi1 and cellular response to gemcitabine.
title_short Ubiquitination and degradation of ribonucleotide reductase M1 by the polycomb group proteins RNF2 and Bmi1 and cellular response to gemcitabine.
title_full Ubiquitination and degradation of ribonucleotide reductase M1 by the polycomb group proteins RNF2 and Bmi1 and cellular response to gemcitabine.
title_fullStr Ubiquitination and degradation of ribonucleotide reductase M1 by the polycomb group proteins RNF2 and Bmi1 and cellular response to gemcitabine.
title_full_unstemmed Ubiquitination and degradation of ribonucleotide reductase M1 by the polycomb group proteins RNF2 and Bmi1 and cellular response to gemcitabine.
title_sort ubiquitination and degradation of ribonucleotide reductase m1 by the polycomb group proteins rnf2 and bmi1 and cellular response to gemcitabine.
publisher Public Library of Science (PLoS)
publishDate 2014
url https://doaj.org/article/baf60fec75ac48fea5e00121a55b4879
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AT xinli ubiquitinationanddegradationofribonucleotidereductasem1bythepolycombgroupproteinsrnf2andbmi1andcellularresponsetogemcitabine
AT zhengmingchen ubiquitinationanddegradationofribonucleotidereductasem1bythepolycombgroupproteinsrnf2andbmi1andcellularresponsetogemcitabine
AT geroldbepler ubiquitinationanddegradationofribonucleotidereductasem1bythepolycombgroupproteinsrnf2andbmi1andcellularresponsetogemcitabine
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