The Haploinsufficient Tumor Suppressor p18 Upregulates p53 via Interactions with ATM/ATR
p18 was first identified as a factor associated with a macromolecular tRNA synthetase complex. Here we describe the mouse p18 loss-of-function phenotype and a role for p18 in the DNA damage response. Inactivation of both p18 alleles caused embryonic lethality, while heterozygous mice showed high sus...
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Veröffentlicht in: | Cell 2005-01, Vol.120 (2), p.209-221 |
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description | p18 was first identified as a factor associated with a macromolecular tRNA synthetase complex. Here we describe the mouse p18 loss-of-function phenotype and a role for p18 in the DNA damage response. Inactivation of both p18 alleles caused embryonic lethality, while heterozygous mice showed high susceptibility to spontaneous tumors. p18 was induced and translocated to the nucleus in response to DNA damage. Expression of p18 resulted in elevated p53 levels, while p18 depletion blocked p53 induction. p18 directly interacted with ATM/ATR in response to DNA damage. The activity of ATM was dependent on the level of p18, suggesting the requirement of p18 for the activation of ATM. Low p18 expression was frequently observed in different human cancer cell lines and tissues. These results suggest that p18 is a haploinsufficient tumor suppressor and a key factor for ATM/ATR-mediated p53 activation. |
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Here we describe the mouse p18 loss-of-function phenotype and a role for p18 in the DNA damage response. Inactivation of both p18 alleles caused embryonic lethality, while heterozygous mice showed high susceptibility to spontaneous tumors. p18 was induced and translocated to the nucleus in response to DNA damage. Expression of p18 resulted in elevated p53 levels, while p18 depletion blocked p53 induction. p18 directly interacted with ATM/ATR in response to DNA damage. The activity of ATM was dependent on the level of p18, suggesting the requirement of p18 for the activation of ATM. Low p18 expression was frequently observed in different human cancer cell lines and tissues. These results suggest that p18 is a haploinsufficient tumor suppressor and a key factor for ATM/ATR-mediated p53 activation.</description><identifier>ISSN: 0092-8674</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/j.cell.2004.11.054</identifier><identifier>PMID: 15680327</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Alleles ; Amino Acyl-tRNA Synthetases - metabolism ; Animals ; Apoptosis - physiology ; Ataxia Telangiectasia Mutated Proteins ; Base Sequence ; Cell Cycle - physiology ; Cell Cycle Proteins - metabolism ; Cell Nucleus - metabolism ; Cell Proliferation ; DNA Damage - physiology ; DNA-Binding Proteins ; Gene Expression Regulation, Neoplastic - physiology ; Humans ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Protein-Serine-Threonine Kinases - metabolism ; Tumor Cells, Cultured ; Tumor Suppressor Protein p53 - metabolism ; Tumor Suppressor Proteins</subject><ispartof>Cell, 2005-01, Vol.120 (2), p.209-221</ispartof><rights>2005 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c429t-32dd8dfa873a306eb048a2844b7b8f4f971f1fae62fb78f9f8f7cb524794d8513</citedby><cites>FETCH-LOGICAL-c429t-32dd8dfa873a306eb048a2844b7b8f4f971f1fae62fb78f9f8f7cb524794d8513</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.cell.2004.11.054$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15680327$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Park, Bum-Joon</creatorcontrib><creatorcontrib>Kang, Jin Wook</creatorcontrib><creatorcontrib>Lee, Sang Won</creatorcontrib><creatorcontrib>Choi, So-Jung</creatorcontrib><creatorcontrib>Shin, Young Kee</creatorcontrib><creatorcontrib>Ahn, Young Ha</creatorcontrib><creatorcontrib>Choi, Yun Hee</creatorcontrib><creatorcontrib>Choi, Dongho</creatorcontrib><creatorcontrib>Lee, Kwang Soo</creatorcontrib><creatorcontrib>Kim, Sunghoon</creatorcontrib><title>The Haploinsufficient Tumor Suppressor p18 Upregulates p53 via Interactions with ATM/ATR</title><title>Cell</title><addtitle>Cell</addtitle><description>p18 was first identified as a factor associated with a macromolecular tRNA synthetase complex. 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These results suggest that p18 is a haploinsufficient tumor suppressor and a key factor for ATM/ATR-mediated p53 activation.</description><subject>Alleles</subject><subject>Amino Acyl-tRNA Synthetases - metabolism</subject><subject>Animals</subject><subject>Apoptosis - physiology</subject><subject>Ataxia Telangiectasia Mutated Proteins</subject><subject>Base Sequence</subject><subject>Cell Cycle - physiology</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Cell Nucleus - metabolism</subject><subject>Cell Proliferation</subject><subject>DNA Damage - physiology</subject><subject>DNA-Binding Proteins</subject><subject>Gene Expression Regulation, Neoplastic - physiology</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Molecular Sequence Data</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Tumor Cells, Cultured</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumor Suppressor Proteins</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkMFq3DAURUVpaCZpf6CLolV3dvQk2ZKhmyGkSSAhkHigOyHbTx0NHtuV7JT8fWxmILtkpSc49ywOId-BpcAgv9ilNbZtyhmTKUDKMvmJrIAVKpGg-GeyYqzgic6VPCVnMe4YYzrLsi_kFLJcM8HVivwpt0hv7ND2vouTc7722I20nPZ9oE_TMASMcT4H0HQzf_5OrR0x0iET9NlbetuNGGw9-r6L9L8ft3Rd3l-sy8ev5MTZNuK343tONr-vysub5O7h-vZyfZfUkhdjInjT6MZZrYQVLMeKSW25lrJSlXbSFQocOIs5d5XSrnDaqbrKuFSFbHQG4pz8PHiH0P-bMI5m7-PSxXbYT9HkShTAhPwQBJWDyNVi5AewDn2MAZ0Zgt_b8GKAmSW82ZllZ5bwBsDM4efRj6N9qvbYvE2OpWfg1wHAOcazx2DikrrGxgesR9P0_j3_K25Lk7c</recordid><startdate>20050128</startdate><enddate>20050128</enddate><creator>Park, Bum-Joon</creator><creator>Kang, Jin Wook</creator><creator>Lee, Sang Won</creator><creator>Choi, So-Jung</creator><creator>Shin, Young Kee</creator><creator>Ahn, Young Ha</creator><creator>Choi, Yun Hee</creator><creator>Choi, Dongho</creator><creator>Lee, Kwang Soo</creator><creator>Kim, Sunghoon</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>7TM</scope><scope>7TO</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20050128</creationdate><title>The Haploinsufficient Tumor Suppressor p18 Upregulates p53 via Interactions with ATM/ATR</title><author>Park, Bum-Joon ; Kang, Jin Wook ; Lee, Sang Won ; Choi, So-Jung ; Shin, Young Kee ; Ahn, Young Ha ; Choi, Yun Hee ; Choi, Dongho ; Lee, Kwang Soo ; Kim, Sunghoon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c429t-32dd8dfa873a306eb048a2844b7b8f4f971f1fae62fb78f9f8f7cb524794d8513</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Alleles</topic><topic>Amino Acyl-tRNA Synthetases - metabolism</topic><topic>Animals</topic><topic>Apoptosis - physiology</topic><topic>Ataxia Telangiectasia Mutated Proteins</topic><topic>Base Sequence</topic><topic>Cell Cycle - physiology</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Cell Nucleus - metabolism</topic><topic>Cell Proliferation</topic><topic>DNA Damage - physiology</topic><topic>DNA-Binding Proteins</topic><topic>Gene Expression Regulation, Neoplastic - physiology</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Molecular Sequence Data</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Tumor Cells, Cultured</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumor Suppressor Proteins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Park, Bum-Joon</creatorcontrib><creatorcontrib>Kang, Jin Wook</creatorcontrib><creatorcontrib>Lee, Sang Won</creatorcontrib><creatorcontrib>Choi, So-Jung</creatorcontrib><creatorcontrib>Shin, Young Kee</creatorcontrib><creatorcontrib>Ahn, Young Ha</creatorcontrib><creatorcontrib>Choi, Yun Hee</creatorcontrib><creatorcontrib>Choi, Dongho</creatorcontrib><creatorcontrib>Lee, Kwang Soo</creatorcontrib><creatorcontrib>Kim, Sunghoon</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>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Park, Bum-Joon</au><au>Kang, Jin Wook</au><au>Lee, Sang Won</au><au>Choi, So-Jung</au><au>Shin, Young Kee</au><au>Ahn, Young Ha</au><au>Choi, Yun Hee</au><au>Choi, Dongho</au><au>Lee, Kwang Soo</au><au>Kim, Sunghoon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Haploinsufficient Tumor Suppressor p18 Upregulates p53 via Interactions with ATM/ATR</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2005-01-28</date><risdate>2005</risdate><volume>120</volume><issue>2</issue><spage>209</spage><epage>221</epage><pages>209-221</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><abstract>p18 was first identified as a factor associated with a macromolecular tRNA synthetase complex. Here we describe the mouse p18 loss-of-function phenotype and a role for p18 in the DNA damage response. Inactivation of both p18 alleles caused embryonic lethality, while heterozygous mice showed high susceptibility to spontaneous tumors. p18 was induced and translocated to the nucleus in response to DNA damage. Expression of p18 resulted in elevated p53 levels, while p18 depletion blocked p53 induction. p18 directly interacted with ATM/ATR in response to DNA damage. The activity of ATM was dependent on the level of p18, suggesting the requirement of p18 for the activation of ATM. Low p18 expression was frequently observed in different human cancer cell lines and tissues. These results suggest that p18 is a haploinsufficient tumor suppressor and a key factor for ATM/ATR-mediated p53 activation.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>15680327</pmid><doi>10.1016/j.cell.2004.11.054</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Alleles Amino Acyl-tRNA Synthetases - metabolism Animals Apoptosis - physiology Ataxia Telangiectasia Mutated Proteins Base Sequence Cell Cycle - physiology Cell Cycle Proteins - metabolism Cell Nucleus - metabolism Cell Proliferation DNA Damage - physiology DNA-Binding Proteins Gene Expression Regulation, Neoplastic - physiology Humans Mice Mice, Knockout Molecular Sequence Data Protein-Serine-Threonine Kinases - metabolism Tumor Cells, Cultured Tumor Suppressor Protein p53 - metabolism Tumor Suppressor Proteins |
title | The Haploinsufficient Tumor Suppressor p18 Upregulates p53 via Interactions with ATM/ATR |
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