MDM2 Promotes Proteasome-Dependent Ubiquitin-Independent Degradation of Retinoblastoma Protein
Inactivation of retinoblastoma protein (Rb) plays a critical role in the development of human malignancies. It has been shown that Rb is degraded through a proteasome-dependent pathway, yet the mechanism is largely unclear. MDM2 is frequently found amplified and overexpressed in a variety of human t...
Gespeichert in:
| Veröffentlicht in: | Molecular cell 2005-12, Vol.20 (5), p.699-708 |
|---|---|
| Hauptverfasser: | , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 708 |
|---|---|
| container_issue | 5 |
| container_start_page | 699 |
| container_title | Molecular cell |
| container_volume | 20 |
| creator | Sdek, Patima Ying, Haoqiang Chang, Donny L.F. Qiu, Wei Zheng, Hongwu Touitou, Robert Allday, Martin J. Jim Xiao, Zhi-Xiong |
| description | Inactivation of retinoblastoma protein (Rb) plays a critical role in the development of human malignancies. It has been shown that Rb is degraded through a proteasome-dependent pathway, yet the mechanism is largely unclear. MDM2 is frequently found amplified and overexpressed in a variety of human tumors. In this study, we find that MDM2 promotes Rb degradation in a proteasome-dependent and ubiquitin-independent manner. We show that Rb, MDM2, and the C8 subunit of the 20S proteasome interact in vitro and in vivo and that MDM2 promotes Rb-C8 interaction. Expression of wild-type MDM2, but not the mutant MDM2 defective either in Rb interaction or in RING finger domain, promotes cell cycle S phase entry independent of p53. Furthermore, MDM2 ablation results in Rb accumulation and inhibition of DNA synthesis. Taken together, these findings demonstrate that MDM2 is a critical negative regulator for Rb and suggest that MDM2 overexpression contributes to cancer development by destabilizing Rb. |
| doi_str_mv | 10.1016/j.molcel.2005.10.017 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_68885329</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1097276505016874</els_id><sourcerecordid>68885329</sourcerecordid><originalsourceid>FETCH-LOGICAL-c406t-4672a6a2b6dc91000c4dabbb143b03098397bc3a8e875f6780b4d058fde745763</originalsourceid><addsrcrecordid>eNp9kE1r3DAQhkVJ6CZp_kEJe8rN25EtS_KlULJtGkhIKN1rhD7GRYttbSRtIP--Wryht540vDzzinkI-UxhRYHyL9vVGAaLw6oGaEu0Aio-kDMKnagY5ezkONeCtwtyntIWgLJWdh_JgvKmEW3Hzsjzw_qhXj7FMIaM6TBk1CmMWK1xh5PDKS83xr_sffZTdVeC93SNf6J2OvswLUO__IUFCGbQKYdRz0V--kROez0kvDy-F2Tz4_vvm5_V_ePt3c23-8oy4LliXNSa69pwZzsKAJY5bYyhrDHQQCebThjbaIlStD0XEgxz0MreoWCt4M0FuZ57dzG87DFlNfpU5Ax6wrBPiksp26buCshm0MaQUsRe7aIfdXxTFNTBq9qq2as6eD2kxWtZuzr2782I7t_SUWQBvs4AlitfPUaVrMfJovMRbVYu-P__8Bf0novl</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>68885329</pqid></control><display><type>article</type><title>MDM2 Promotes Proteasome-Dependent Ubiquitin-Independent Degradation of Retinoblastoma Protein</title><source>MEDLINE</source><source>Cell Press Free Archives</source><source>Elsevier ScienceDirect Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Free Full-Text Journals in Chemistry</source><creator>Sdek, Patima ; Ying, Haoqiang ; Chang, Donny L.F. ; Qiu, Wei ; Zheng, Hongwu ; Touitou, Robert ; Allday, Martin J. ; Jim Xiao, Zhi-Xiong</creator><creatorcontrib>Sdek, Patima ; Ying, Haoqiang ; Chang, Donny L.F. ; Qiu, Wei ; Zheng, Hongwu ; Touitou, Robert ; Allday, Martin J. ; Jim Xiao, Zhi-Xiong</creatorcontrib><description>Inactivation of retinoblastoma protein (Rb) plays a critical role in the development of human malignancies. It has been shown that Rb is degraded through a proteasome-dependent pathway, yet the mechanism is largely unclear. MDM2 is frequently found amplified and overexpressed in a variety of human tumors. In this study, we find that MDM2 promotes Rb degradation in a proteasome-dependent and ubiquitin-independent manner. We show that Rb, MDM2, and the C8 subunit of the 20S proteasome interact in vitro and in vivo and that MDM2 promotes Rb-C8 interaction. Expression of wild-type MDM2, but not the mutant MDM2 defective either in Rb interaction or in RING finger domain, promotes cell cycle S phase entry independent of p53. Furthermore, MDM2 ablation results in Rb accumulation and inhibition of DNA synthesis. Taken together, these findings demonstrate that MDM2 is a critical negative regulator for Rb and suggest that MDM2 overexpression contributes to cancer development by destabilizing Rb.</description><identifier>ISSN: 1097-2765</identifier><identifier>EISSN: 1097-4164</identifier><identifier>DOI: 10.1016/j.molcel.2005.10.017</identifier><identifier>PMID: 16337594</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Cell Line, Tumor ; Cysteine Endopeptidases - metabolism ; DNA - biosynthesis ; DNA - drug effects ; Gamma Rays ; Humans ; In Vitro Techniques ; Proteasome Endopeptidase Complex - metabolism ; Proto-Oncogene Proteins c-mdm2 - metabolism ; Proto-Oncogene Proteins c-mdm2 - pharmacology ; Proto-Oncogene Proteins c-mdm2 - radiation effects ; Retinoblastoma Protein - drug effects ; Retinoblastoma Protein - metabolism ; S Phase - physiology ; S Phase - radiation effects ; Ubiquitin - metabolism</subject><ispartof>Molecular cell, 2005-12, Vol.20 (5), p.699-708</ispartof><rights>2005 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c406t-4672a6a2b6dc91000c4dabbb143b03098397bc3a8e875f6780b4d058fde745763</citedby><cites>FETCH-LOGICAL-c406t-4672a6a2b6dc91000c4dabbb143b03098397bc3a8e875f6780b4d058fde745763</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1097276505016874$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16337594$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sdek, Patima</creatorcontrib><creatorcontrib>Ying, Haoqiang</creatorcontrib><creatorcontrib>Chang, Donny L.F.</creatorcontrib><creatorcontrib>Qiu, Wei</creatorcontrib><creatorcontrib>Zheng, Hongwu</creatorcontrib><creatorcontrib>Touitou, Robert</creatorcontrib><creatorcontrib>Allday, Martin J.</creatorcontrib><creatorcontrib>Jim Xiao, Zhi-Xiong</creatorcontrib><title>MDM2 Promotes Proteasome-Dependent Ubiquitin-Independent Degradation of Retinoblastoma Protein</title><title>Molecular cell</title><addtitle>Mol Cell</addtitle><description>Inactivation of retinoblastoma protein (Rb) plays a critical role in the development of human malignancies. It has been shown that Rb is degraded through a proteasome-dependent pathway, yet the mechanism is largely unclear. MDM2 is frequently found amplified and overexpressed in a variety of human tumors. In this study, we find that MDM2 promotes Rb degradation in a proteasome-dependent and ubiquitin-independent manner. We show that Rb, MDM2, and the C8 subunit of the 20S proteasome interact in vitro and in vivo and that MDM2 promotes Rb-C8 interaction. Expression of wild-type MDM2, but not the mutant MDM2 defective either in Rb interaction or in RING finger domain, promotes cell cycle S phase entry independent of p53. Furthermore, MDM2 ablation results in Rb accumulation and inhibition of DNA synthesis. Taken together, these findings demonstrate that MDM2 is a critical negative regulator for Rb and suggest that MDM2 overexpression contributes to cancer development by destabilizing Rb.</description><subject>Cell Line, Tumor</subject><subject>Cysteine Endopeptidases - metabolism</subject><subject>DNA - biosynthesis</subject><subject>DNA - drug effects</subject><subject>Gamma Rays</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Proto-Oncogene Proteins c-mdm2 - metabolism</subject><subject>Proto-Oncogene Proteins c-mdm2 - pharmacology</subject><subject>Proto-Oncogene Proteins c-mdm2 - radiation effects</subject><subject>Retinoblastoma Protein - drug effects</subject><subject>Retinoblastoma Protein - metabolism</subject><subject>S Phase - physiology</subject><subject>S Phase - radiation effects</subject><subject>Ubiquitin - metabolism</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1r3DAQhkVJ6CZp_kEJe8rN25EtS_KlULJtGkhIKN1rhD7GRYttbSRtIP--Wryht540vDzzinkI-UxhRYHyL9vVGAaLw6oGaEu0Aio-kDMKnagY5ezkONeCtwtyntIWgLJWdh_JgvKmEW3Hzsjzw_qhXj7FMIaM6TBk1CmMWK1xh5PDKS83xr_sffZTdVeC93SNf6J2OvswLUO__IUFCGbQKYdRz0V--kROez0kvDy-F2Tz4_vvm5_V_ePt3c23-8oy4LliXNSa69pwZzsKAJY5bYyhrDHQQCebThjbaIlStD0XEgxz0MreoWCt4M0FuZ57dzG87DFlNfpU5Ax6wrBPiksp26buCshm0MaQUsRe7aIfdXxTFNTBq9qq2as6eD2kxWtZuzr2782I7t_SUWQBvs4AlitfPUaVrMfJovMRbVYu-P__8Bf0novl</recordid><startdate>20051209</startdate><enddate>20051209</enddate><creator>Sdek, Patima</creator><creator>Ying, Haoqiang</creator><creator>Chang, Donny L.F.</creator><creator>Qiu, Wei</creator><creator>Zheng, Hongwu</creator><creator>Touitou, Robert</creator><creator>Allday, Martin J.</creator><creator>Jim Xiao, Zhi-Xiong</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><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>20051209</creationdate><title>MDM2 Promotes Proteasome-Dependent Ubiquitin-Independent Degradation of Retinoblastoma Protein</title><author>Sdek, Patima ; Ying, Haoqiang ; Chang, Donny L.F. ; Qiu, Wei ; Zheng, Hongwu ; Touitou, Robert ; Allday, Martin J. ; Jim Xiao, Zhi-Xiong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c406t-4672a6a2b6dc91000c4dabbb143b03098397bc3a8e875f6780b4d058fde745763</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Cell Line, Tumor</topic><topic>Cysteine Endopeptidases - metabolism</topic><topic>DNA - biosynthesis</topic><topic>DNA - drug effects</topic><topic>Gamma Rays</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Proteasome Endopeptidase Complex - metabolism</topic><topic>Proto-Oncogene Proteins c-mdm2 - metabolism</topic><topic>Proto-Oncogene Proteins c-mdm2 - pharmacology</topic><topic>Proto-Oncogene Proteins c-mdm2 - radiation effects</topic><topic>Retinoblastoma Protein - drug effects</topic><topic>Retinoblastoma Protein - metabolism</topic><topic>S Phase - physiology</topic><topic>S Phase - radiation effects</topic><topic>Ubiquitin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sdek, Patima</creatorcontrib><creatorcontrib>Ying, Haoqiang</creatorcontrib><creatorcontrib>Chang, Donny L.F.</creatorcontrib><creatorcontrib>Qiu, Wei</creatorcontrib><creatorcontrib>Zheng, Hongwu</creatorcontrib><creatorcontrib>Touitou, Robert</creatorcontrib><creatorcontrib>Allday, Martin J.</creatorcontrib><creatorcontrib>Jim Xiao, Zhi-Xiong</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><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>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sdek, Patima</au><au>Ying, Haoqiang</au><au>Chang, Donny L.F.</au><au>Qiu, Wei</au><au>Zheng, Hongwu</au><au>Touitou, Robert</au><au>Allday, Martin J.</au><au>Jim Xiao, Zhi-Xiong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MDM2 Promotes Proteasome-Dependent Ubiquitin-Independent Degradation of Retinoblastoma Protein</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2005-12-09</date><risdate>2005</risdate><volume>20</volume><issue>5</issue><spage>699</spage><epage>708</epage><pages>699-708</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>Inactivation of retinoblastoma protein (Rb) plays a critical role in the development of human malignancies. It has been shown that Rb is degraded through a proteasome-dependent pathway, yet the mechanism is largely unclear. MDM2 is frequently found amplified and overexpressed in a variety of human tumors. In this study, we find that MDM2 promotes Rb degradation in a proteasome-dependent and ubiquitin-independent manner. We show that Rb, MDM2, and the C8 subunit of the 20S proteasome interact in vitro and in vivo and that MDM2 promotes Rb-C8 interaction. Expression of wild-type MDM2, but not the mutant MDM2 defective either in Rb interaction or in RING finger domain, promotes cell cycle S phase entry independent of p53. Furthermore, MDM2 ablation results in Rb accumulation and inhibition of DNA synthesis. Taken together, these findings demonstrate that MDM2 is a critical negative regulator for Rb and suggest that MDM2 overexpression contributes to cancer development by destabilizing Rb.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>16337594</pmid><doi>10.1016/j.molcel.2005.10.017</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1097-2765 |
| ispartof | Molecular cell, 2005-12, Vol.20 (5), p.699-708 |
| issn | 1097-2765 1097-4164 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_68885329 |
| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Free Full-Text Journals in Chemistry |
| subjects | Cell Line, Tumor Cysteine Endopeptidases - metabolism DNA - biosynthesis DNA - drug effects Gamma Rays Humans In Vitro Techniques Proteasome Endopeptidase Complex - metabolism Proto-Oncogene Proteins c-mdm2 - metabolism Proto-Oncogene Proteins c-mdm2 - pharmacology Proto-Oncogene Proteins c-mdm2 - radiation effects Retinoblastoma Protein - drug effects Retinoblastoma Protein - metabolism S Phase - physiology S Phase - radiation effects Ubiquitin - metabolism |
| title | MDM2 Promotes Proteasome-Dependent Ubiquitin-Independent Degradation of Retinoblastoma Protein |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T07%3A36%3A58IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=MDM2%20Promotes%20Proteasome-Dependent%20Ubiquitin-Independent%20Degradation%20of%20Retinoblastoma%20Protein&rft.jtitle=Molecular%20cell&rft.au=Sdek,%20Patima&rft.date=2005-12-09&rft.volume=20&rft.issue=5&rft.spage=699&rft.epage=708&rft.pages=699-708&rft.issn=1097-2765&rft.eissn=1097-4164&rft_id=info:doi/10.1016/j.molcel.2005.10.017&rft_dat=%3Cproquest_cross%3E68885329%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=68885329&rft_id=info:pmid/16337594&rft_els_id=S1097276505016874&rfr_iscdi=true |