Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization
Mdm2 is a nucleoplasmic and nucleolar protein interacting with p53 and alternative reading frame (ARF) tumor suppressor proteins. Here we demonstrate relocalization and novel interactions of Mdm2 with the promyelocytic leukemia (PML) protein following cellular stress and DNA damage. We show that Mdm...
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Veröffentlicht in: | Journal of cell science 2003-10, Vol.116 (Pt 19), p.3917-3925 |
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creator | Kurki, Sari Latonen, Leena Laiho, Marikki |
description | Mdm2 is a nucleoplasmic and nucleolar protein interacting with p53 and alternative reading frame (ARF) tumor suppressor proteins. Here we demonstrate relocalization and novel interactions of Mdm2 with the promyelocytic leukemia (PML) protein following cellular stress and DNA damage. We show that Mdm2 and PML interact directly in vivo and in vitro depending on the Mdm2 RING finger domain and the PML C-terminus, and that Mdm2 is recruited to the PML nuclear bodies by overexpression of PML. Cellular stress and DNA damage caused by UV-radiation, downregulation of the proteasome and arsenic trioxide promoted Mdm2 and PML damage-specific nuclear relocalization and interaction in a p53-independent manner. However, in vitro analyses showed that PML, Mdm2 and p53 form trimeric complexes. UV-radiation caused rapid rearrangements of PML nuclear bodies and promoted PML-p53 and PML-Mdm2 complex formation, coinciding with p53 stabilization and preceding p53-Mdm2 interaction suggesting temporally distinct complexes. The results demonstrate novel associations between Mdm2 and PML and show the capacity of PML to participate in the activation and stabilization of p53 in response to cellular stress through PML interaction with Mdm2. |
doi_str_mv | 10.1242/jcs.00714 |
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Here we demonstrate relocalization and novel interactions of Mdm2 with the promyelocytic leukemia (PML) protein following cellular stress and DNA damage. We show that Mdm2 and PML interact directly in vivo and in vitro depending on the Mdm2 RING finger domain and the PML C-terminus, and that Mdm2 is recruited to the PML nuclear bodies by overexpression of PML. Cellular stress and DNA damage caused by UV-radiation, downregulation of the proteasome and arsenic trioxide promoted Mdm2 and PML damage-specific nuclear relocalization and interaction in a p53-independent manner. However, in vitro analyses showed that PML, Mdm2 and p53 form trimeric complexes. UV-radiation caused rapid rearrangements of PML nuclear bodies and promoted PML-p53 and PML-Mdm2 complex formation, coinciding with p53 stabilization and preceding p53-Mdm2 interaction suggesting temporally distinct complexes. The results demonstrate novel associations between Mdm2 and PML and show the capacity of PML to participate in the activation and stabilization of p53 in response to cellular stress through PML interaction with Mdm2.</description><subject>Animals</subject><subject>Arsenicals - pharmacology</subject><subject>Cells, Cultured</subject><subject>Cyclin-Dependent Kinase Inhibitor p16</subject><subject>DNA Damage - physiology</subject><subject>DNA Damage - radiation effects</subject><subject>Humans</subject><subject>Mice</subject><subject>Microscopy, Fluorescence</subject><subject>Nuclear Matrix - drug effects</subject><subject>Nuclear Matrix - metabolism</subject><subject>Nuclear Matrix - radiation effects</subject><subject>Nuclear Proteins - metabolism</subject><subject>Oxides - pharmacology</subject><subject>Protein Binding - drug effects</subject><subject>Protein Binding - radiation effects</subject><subject>Protein Structure, Tertiary</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-mdm2</subject><subject>Tumor Suppressor Protein p14ARF - metabolism</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Ultraviolet Rays</subject><issn>0021-9533</issn><issn>1477-9137</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkD1PwzAQQC0EoqUw8AeQJyQkUmxfUjdjVT6lFhhgjlz7glycD-wEUSZ-OqGphJdb3r2THyGnnI25iMXVWocxY5LHe2TIYymjlIPcJ0PGBI_SBGBAjkJYs44RqTwkAy5SniQpG5KfOTrXOuVpaDyGQFVp6PXjjBpVqDektvys3pE2WNSVV85tqLGhsaVu6NIU4pLWCWx3npcLqquidviFvaU3RKFGbXOradlqh90hj67Sytlv1diqPCYHuXIBT3ZzRF5vb17m99Hi6e5hPltEGhJoIskMShAGtF4hj0WuGaCUyITuHkx5glPG9ZSLnOeQq4mSCdPpxPBVngImMCLnvbf21UeLockKG3T3eVVi1YZMwkQISKEDL3pQ-yoEj3lWe1sov8k4y_5yZ13ubJu7Y8920nZVoPknd33hF2jdfDc</recordid><startdate>20031001</startdate><enddate>20031001</enddate><creator>Kurki, Sari</creator><creator>Latonen, Leena</creator><creator>Laiho, Marikki</creator><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>7X8</scope></search><sort><creationdate>20031001</creationdate><title>Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization</title><author>Kurki, Sari ; Latonen, Leena ; Laiho, Marikki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-70de732d3ccbe142fc03e77e02cccc3815e801c812f1f3fa6a750c96d1bf93e53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Arsenicals - pharmacology</topic><topic>Cells, Cultured</topic><topic>Cyclin-Dependent Kinase Inhibitor p16</topic><topic>DNA Damage - physiology</topic><topic>DNA Damage - radiation effects</topic><topic>Humans</topic><topic>Mice</topic><topic>Microscopy, Fluorescence</topic><topic>Nuclear Matrix - drug effects</topic><topic>Nuclear Matrix - metabolism</topic><topic>Nuclear Matrix - radiation effects</topic><topic>Nuclear Proteins - metabolism</topic><topic>Oxides - pharmacology</topic><topic>Protein Binding - drug effects</topic><topic>Protein Binding - radiation effects</topic><topic>Protein Structure, Tertiary</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-mdm2</topic><topic>Tumor Suppressor Protein p14ARF - metabolism</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Ultraviolet Rays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kurki, Sari</creatorcontrib><creatorcontrib>Latonen, Leena</creatorcontrib><creatorcontrib>Laiho, Marikki</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of cell science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kurki, Sari</au><au>Latonen, Leena</au><au>Laiho, Marikki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization</atitle><jtitle>Journal of cell science</jtitle><addtitle>J Cell Sci</addtitle><date>2003-10-01</date><risdate>2003</risdate><volume>116</volume><issue>Pt 19</issue><spage>3917</spage><epage>3925</epage><pages>3917-3925</pages><issn>0021-9533</issn><eissn>1477-9137</eissn><abstract>Mdm2 is a nucleoplasmic and nucleolar protein interacting with p53 and alternative reading frame (ARF) tumor suppressor proteins. Here we demonstrate relocalization and novel interactions of Mdm2 with the promyelocytic leukemia (PML) protein following cellular stress and DNA damage. We show that Mdm2 and PML interact directly in vivo and in vitro depending on the Mdm2 RING finger domain and the PML C-terminus, and that Mdm2 is recruited to the PML nuclear bodies by overexpression of PML. Cellular stress and DNA damage caused by UV-radiation, downregulation of the proteasome and arsenic trioxide promoted Mdm2 and PML damage-specific nuclear relocalization and interaction in a p53-independent manner. However, in vitro analyses showed that PML, Mdm2 and p53 form trimeric complexes. UV-radiation caused rapid rearrangements of PML nuclear bodies and promoted PML-p53 and PML-Mdm2 complex formation, coinciding with p53 stabilization and preceding p53-Mdm2 interaction suggesting temporally distinct complexes. The results demonstrate novel associations between Mdm2 and PML and show the capacity of PML to participate in the activation and stabilization of p53 in response to cellular stress through PML interaction with Mdm2.</abstract><cop>England</cop><pmid>12915590</pmid><doi>10.1242/jcs.00714</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Company of Biologists |
subjects | Animals Arsenicals - pharmacology Cells, Cultured Cyclin-Dependent Kinase Inhibitor p16 DNA Damage - physiology DNA Damage - radiation effects Humans Mice Microscopy, Fluorescence Nuclear Matrix - drug effects Nuclear Matrix - metabolism Nuclear Matrix - radiation effects Nuclear Proteins - metabolism Oxides - pharmacology Protein Binding - drug effects Protein Binding - radiation effects Protein Structure, Tertiary Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-mdm2 Tumor Suppressor Protein p14ARF - metabolism Tumor Suppressor Protein p53 - metabolism Ultraviolet Rays |
title | Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization |
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