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Overexpression of Mdm2 in Mice Reveals a p53-Independent Role for Mdm2 in Tumorigenesis
The Mdm2 proto-oncogene is amplified to high copy numbers in human sarcomas and is overexpressed in a wide variety of other human cancers. Because Mdm2 protein forms a complex with the p53 tumor suppressor protein and down-regulates p53 function, the oncogenic potential of Mdm2 is presumed to be p53...
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| Published in: | Proceedings of the National Academy of Sciences - PNAS 1998-12, Vol.95 (26), p.15608-15612 |
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| Main Authors: | , , , , |
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| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-c589t-ae8c1594a66c213b26a12439077e0b3bbcedbc76fc307873edd878e486c2f0c33 |
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| cites | cdi_FETCH-LOGICAL-c589t-ae8c1594a66c213b26a12439077e0b3bbcedbc76fc307873edd878e486c2f0c33 |
| container_end_page | 15612 |
| container_issue | 26 |
| container_start_page | 15608 |
| container_title | Proceedings of the National Academy of Sciences - PNAS |
| container_volume | 95 |
| creator | Jones, Stephen N. Hancock, Amy R. Vogel, Hannes Donehower, Lawrence A. Bradley, Allan |
| description | The Mdm2 proto-oncogene is amplified to high copy numbers in human sarcomas and is overexpressed in a wide variety of other human cancers. Because Mdm2 protein forms a complex with the p53 tumor suppressor protein and down-regulates p53 function, the oncogenic potential of Mdm2 is presumed to be p53-dependent. To model these conditions in mice, we have used the entire Mdm2 gene, under transcriptional control of its native promoter region, as a transgene to create mice that overexpress Mdm2. The transgenic mice are predisposed to spontaneous tumor formation, and the incidence of sarcomas observed in the Mdm2-transgenic mice in the presence or absence of functional p53 demonstrates that, in addition to Mdm2-mediated inactivation of p53, there exists a p53-independent role for Mdm2 in tumorigenesis. |
| doi_str_mv | 10.1073/pnas.95.26.15608 |
| format | article |
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Because Mdm2 protein forms a complex with the p53 tumor suppressor protein and down-regulates p53 function, the oncogenic potential of Mdm2 is presumed to be p53-dependent. To model these conditions in mice, we have used the entire Mdm2 gene, under transcriptional control of its native promoter region, as a transgene to create mice that overexpress Mdm2. The transgenic mice are predisposed to spontaneous tumor formation, and the incidence of sarcomas observed in the Mdm2-transgenic mice in the presence or absence of functional p53 demonstrates that, in addition to Mdm2-mediated inactivation of p53, there exists a p53-independent role for Mdm2 in tumorigenesis.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.95.26.15608</identifier><identifier>PMID: 9861017</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>Animals ; Biological Sciences ; Cancer ; Cell growth ; Cell lines ; Cell Transformation, Neoplastic ; Chimera ; Cosmids ; Crosses, Genetic ; Female ; Fibroblasts ; Gene Deletion ; Genes ; Genes, p53 ; Heterozygote ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred Strains ; Mice, Transgenic ; Neoplasm Proteins - metabolism ; Neoplasms, Experimental - genetics ; Neoplasms, Experimental - pathology ; Nuclear Proteins ; Promoter Regions, Genetic ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-mdm2 ; Rodents ; Sarcoma ; Transcription, Genetic ; Transgenes ; Transgenic animals ; Tumor Suppressor Protein p53 - metabolism ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1998-12, Vol.95 (26), p.15608-15612</ispartof><rights>Copyright 1993-1998 National Academy of Sciences</rights><rights>Copyright National Academy of Sciences Dec 22, 1998</rights><rights>Copyright © 1998, The National Academy of Sciences 1998</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c589t-ae8c1594a66c213b26a12439077e0b3bbcedbc76fc307873edd878e486c2f0c33</citedby><cites>FETCH-LOGICAL-c589t-ae8c1594a66c213b26a12439077e0b3bbcedbc76fc307873edd878e486c2f0c33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/95/26.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/46426$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/46426$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768,58213,58446</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9861017$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jones, Stephen N.</creatorcontrib><creatorcontrib>Hancock, Amy R.</creatorcontrib><creatorcontrib>Vogel, Hannes</creatorcontrib><creatorcontrib>Donehower, Lawrence A.</creatorcontrib><creatorcontrib>Bradley, Allan</creatorcontrib><title>Overexpression of Mdm2 in Mice Reveals a p53-Independent Role for Mdm2 in Tumorigenesis</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The Mdm2 proto-oncogene is amplified to high copy numbers in human sarcomas and is overexpressed in a wide variety of other human cancers. Because Mdm2 protein forms a complex with the p53 tumor suppressor protein and down-regulates p53 function, the oncogenic potential of Mdm2 is presumed to be p53-dependent. To model these conditions in mice, we have used the entire Mdm2 gene, under transcriptional control of its native promoter region, as a transgene to create mice that overexpress Mdm2. The transgenic mice are predisposed to spontaneous tumor formation, and the incidence of sarcomas observed in the Mdm2-transgenic mice in the presence or absence of functional p53 demonstrates that, in addition to Mdm2-mediated inactivation of p53, there exists a p53-independent role for Mdm2 in tumorigenesis.</description><subject>Animals</subject><subject>Biological Sciences</subject><subject>Cancer</subject><subject>Cell growth</subject><subject>Cell lines</subject><subject>Cell Transformation, Neoplastic</subject><subject>Chimera</subject><subject>Cosmids</subject><subject>Crosses, Genetic</subject><subject>Female</subject><subject>Fibroblasts</subject><subject>Gene Deletion</subject><subject>Genes</subject><subject>Genes, p53</subject><subject>Heterozygote</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Inbred Strains</subject><subject>Mice, Transgenic</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Neoplasms, Experimental - genetics</subject><subject>Neoplasms, Experimental - pathology</subject><subject>Nuclear Proteins</subject><subject>Promoter Regions, Genetic</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-mdm2</subject><subject>Rodents</subject><subject>Sarcoma</subject><subject>Transcription, Genetic</subject><subject>Transgenes</subject><subject>Transgenic animals</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><recordid>eNqFkcuL1EAQxhtR1nH1LoIYPIiXjNWP9AO8yOJjYZeFZcVj0-lU1gyZdOxOhvW_t8cZ4uOgFHQdvt9XVNdHyFMKawqKvxkHl9amWjO5ppUEfY-sKBhaSmHgPlkBMFVqwcRD8iilDQCYSsMJOTFaUqBqRb5c7TDi3RgxpS4MRWiLy2bLim4oLjuPxTXu0PWpcMVY8fJ8aHDE_AxTcR16LNoQF_5m3obY3eKAqUuPyYM2-_DJsZ-Szx_e35x9Ki-uPp6fvbsofaXNVDrUnlZGOCk9o7xm0lEmuAGlEGpe1x6b2ivZeg5KK45No5VGoTPeguf8lLw9zB3neouNz5tF19sxdlsXv9vgOvunMnRf7W3YWabznbL91dEew7cZ02S3XfLY927AMCcrDQW-r_-BVFEhjJIZfPkXuAlzHPINLAPKqWIVyxAcIB9DShHbZWEKdh-s3QdrTWWZtD-DzZbnv390MRyTzPrro753LuqvCbad-37CuymjL_6NZuLZgdikKcQFEVIwyX8A2snAAw</recordid><startdate>19981222</startdate><enddate>19981222</enddate><creator>Jones, Stephen N.</creator><creator>Hancock, Amy R.</creator><creator>Vogel, Hannes</creator><creator>Donehower, Lawrence A.</creator><creator>Bradley, Allan</creator><general>National Academy of Sciences of the United States of America</general><general>National Acad Sciences</general><general>National Academy of Sciences</general><general>The National Academy of Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>19981222</creationdate><title>Overexpression of Mdm2 in Mice Reveals a p53-Independent Role for Mdm2 in Tumorigenesis</title><author>Jones, Stephen N. ; Hancock, Amy R. ; Vogel, Hannes ; Donehower, Lawrence A. ; Bradley, Allan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c589t-ae8c1594a66c213b26a12439077e0b3bbcedbc76fc307873edd878e486c2f0c33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Animals</topic><topic>Biological Sciences</topic><topic>Cancer</topic><topic>Cell growth</topic><topic>Cell lines</topic><topic>Cell Transformation, Neoplastic</topic><topic>Chimera</topic><topic>Cosmids</topic><topic>Crosses, Genetic</topic><topic>Female</topic><topic>Fibroblasts</topic><topic>Gene Deletion</topic><topic>Genes</topic><topic>Genes, p53</topic><topic>Heterozygote</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Inbred Strains</topic><topic>Mice, Transgenic</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Neoplasms, Experimental - genetics</topic><topic>Neoplasms, Experimental - pathology</topic><topic>Nuclear Proteins</topic><topic>Promoter Regions, Genetic</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-mdm2</topic><topic>Rodents</topic><topic>Sarcoma</topic><topic>Transcription, Genetic</topic><topic>Transgenes</topic><topic>Transgenic animals</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jones, Stephen N.</creatorcontrib><creatorcontrib>Hancock, Amy R.</creatorcontrib><creatorcontrib>Vogel, Hannes</creatorcontrib><creatorcontrib>Donehower, Lawrence A.</creatorcontrib><creatorcontrib>Bradley, Allan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jones, Stephen N.</au><au>Hancock, Amy R.</au><au>Vogel, Hannes</au><au>Donehower, Lawrence A.</au><au>Bradley, Allan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Overexpression of Mdm2 in Mice Reveals a p53-Independent Role for Mdm2 in Tumorigenesis</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>1998-12-22</date><risdate>1998</risdate><volume>95</volume><issue>26</issue><spage>15608</spage><epage>15612</epage><pages>15608-15612</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The Mdm2 proto-oncogene is amplified to high copy numbers in human sarcomas and is overexpressed in a wide variety of other human cancers. Because Mdm2 protein forms a complex with the p53 tumor suppressor protein and down-regulates p53 function, the oncogenic potential of Mdm2 is presumed to be p53-dependent. To model these conditions in mice, we have used the entire Mdm2 gene, under transcriptional control of its native promoter region, as a transgene to create mice that overexpress Mdm2. The transgenic mice are predisposed to spontaneous tumor formation, and the incidence of sarcomas observed in the Mdm2-transgenic mice in the presence or absence of functional p53 demonstrates that, in addition to Mdm2-mediated inactivation of p53, there exists a p53-independent role for Mdm2 in tumorigenesis.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>9861017</pmid><doi>10.1073/pnas.95.26.15608</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 1998-12, Vol.95 (26), p.15608-15612 |
| issn | 0027-8424 1091-6490 |
| language | eng |
| recordid | cdi_crossref_primary_10_1073_pnas_95_26_15608 |
| source | JSTOR Archival Journals and Primary Sources Collection; PubMed Central |
| subjects | Animals Biological Sciences Cancer Cell growth Cell lines Cell Transformation, Neoplastic Chimera Cosmids Crosses, Genetic Female Fibroblasts Gene Deletion Genes Genes, p53 Heterozygote Humans Male Mice Mice, Inbred C57BL Mice, Inbred Strains Mice, Transgenic Neoplasm Proteins - metabolism Neoplasms, Experimental - genetics Neoplasms, Experimental - pathology Nuclear Proteins Promoter Regions, Genetic Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-mdm2 Rodents Sarcoma Transcription, Genetic Transgenes Transgenic animals Tumor Suppressor Protein p53 - metabolism Tumors |
| title | Overexpression of Mdm2 in Mice Reveals a p53-Independent Role for Mdm2 in Tumorigenesis |
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