Role of the Tripartite Motif Protein 27 in Cancer Development
The tripartite motif family protein 27 (TRIM27) is a transcriptional repressor that interacts with, and attenuates senescence induction by, the retinoblastoma-associated protein (RB1). High expression of TRIM27 was noted in several human cancer types including breast and endometrial cancer, where el...
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| description | The tripartite motif family protein 27 (TRIM27) is a transcriptional repressor that interacts with, and attenuates senescence induction by, the retinoblastoma-associated protein (RB1). High expression of TRIM27 was noted in several human cancer types including breast and endometrial cancer, where elevated TRIM27 expression predicts poor prognosis. Here, we investigated the role of TRIM27 expression in cancer development.
We assessed TRIM27 expression in human cancer using cancer profiling arrays containing paired tumor and normal cRNA (n = 261) as well as in murine skin cancer induced by 7, 12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA). We generated mice with disrupted expression of murine TRIM27 (Trim27(-/-)) and assessed their susceptibility to DMBA/TPA-induced skin tumor development compared with isogenic littermates (n = 26 mice per group). We assessed the effect of Trim27 loss on senescence propensity in mouse embryonic fibroblasts (MEFs) by quantifying cell proliferation alongside senescence markers (senescence-associated β-galactosidase [SA-β-gal] activity and hypertrophic cell morphology). The contribution of RB1 on senescence and cancer susceptibility (n > 20 mice per group) in Trim27(-/-) backgrounds was also assessed. Data were analyzed using the Student's t, χ(2), or log-rank test as indicated. All statistical tests were two-sided.
TRIM27 transcript levels are statistically significantly increased in common human cancers, including colon and lung, vs normal tissues (TRIM27 expression relative to ubiquitin: cancers vs normal tissues, mean = 0.59, 95% confidence interval [CI] = 0.55 to 0.63 vs mean = 0.46, 95% CI =0.43 to 0.49, P < .001) as well as in chemically induced mouse skin cancer compared with matched normal tissue (Trim27 expression relative to Gapdh control: tumor vs normal skin, mean = 4.2, 95% CI = 3.97 to 4.43 vs mean = 0.96, 95% CI = 0.69 to 1.2, P < .001). Trim27(-/-) mice (n = 14) were resistant to chemically induced skin cancer development (eight [57.2%] of 14 mice were tumor free) compared with Trim27(+/+) wild-type littermates (n = 13) (one [7.7%] of 13 mice was tumor free). Trim27(-/-) MEFs show enhanced senescence propensity in response to replicative (percentage of SA-β-gal-positive cells: Trim27(+/+) MEFs vs Trim27(-/-) MEFs, mean = 14.2%, 95% CI = 11.1% to 17.4% vs mean = 53.3%, 95% CI = 48.7% to 57.9%, P < .001) or oncogenic stress (percentage of SA-β-gal-positive cells: Trim27(+/+) MEFs + Ra |
| doi_str_mv | 10.1093/jnci/djs224 |
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We assessed TRIM27 expression in human cancer using cancer profiling arrays containing paired tumor and normal cRNA (n = 261) as well as in murine skin cancer induced by 7, 12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA). We generated mice with disrupted expression of murine TRIM27 (Trim27(-/-)) and assessed their susceptibility to DMBA/TPA-induced skin tumor development compared with isogenic littermates (n = 26 mice per group). We assessed the effect of Trim27 loss on senescence propensity in mouse embryonic fibroblasts (MEFs) by quantifying cell proliferation alongside senescence markers (senescence-associated β-galactosidase [SA-β-gal] activity and hypertrophic cell morphology). The contribution of RB1 on senescence and cancer susceptibility (n > 20 mice per group) in Trim27(-/-) backgrounds was also assessed. Data were analyzed using the Student's t, χ(2), or log-rank test as indicated. All statistical tests were two-sided.
TRIM27 transcript levels are statistically significantly increased in common human cancers, including colon and lung, vs normal tissues (TRIM27 expression relative to ubiquitin: cancers vs normal tissues, mean = 0.59, 95% confidence interval [CI] = 0.55 to 0.63 vs mean = 0.46, 95% CI =0.43 to 0.49, P < .001) as well as in chemically induced mouse skin cancer compared with matched normal tissue (Trim27 expression relative to Gapdh control: tumor vs normal skin, mean = 4.2, 95% CI = 3.97 to 4.43 vs mean = 0.96, 95% CI = 0.69 to 1.2, P < .001). Trim27(-/-) mice (n = 14) were resistant to chemically induced skin cancer development (eight [57.2%] of 14 mice were tumor free) compared with Trim27(+/+) wild-type littermates (n = 13) (one [7.7%] of 13 mice was tumor free). Trim27(-/-) MEFs show enhanced senescence propensity in response to replicative (percentage of SA-β-gal-positive cells: Trim27(+/+) MEFs vs Trim27(-/-) MEFs, mean = 14.2%, 95% CI = 11.1% to 17.4% vs mean = 53.3%, 95% CI = 48.7% to 57.9%, P < .001) or oncogenic stress (percentage of SA-β-gal-positive cells: Trim27(+/+) MEFs + Ras vs Trim27(-/-) MEFs + Ras, mean = 24.0%, 95% CI = 19.9% to 28.1% vs mean = 37.3%, 95% CI = 32.2% to 42.4%, P < .05) compared with Trim27(+/+) MEFs. These responses were alleviated following inactivation of murine RB1 (Rb1). Furthermore, Trim27(-/-) mice are not protected from cancers arising as a consequence of Rb1 deletion (median survival: Trim27(-/-)Rb(+/-) vs Trim27(+/+)Rb(+/-), 14 vs 13 months; difference = 1.0 month, 95% CI = 0.5 to 1.6 months, P = .14).
TRIM27 expression is a modifier of disease incidence and progression relevant to the development of common human cancers and is a potential target for intervention in cancer.</description><identifier>ISSN: 0027-8874</identifier><identifier>ISSN: 1460-2105</identifier><identifier>EISSN: 1460-2105</identifier><identifier>DOI: 10.1093/jnci/djs224</identifier><identifier>PMID: 22556269</identifier><identifier>CODEN: JNCIEQ</identifier><language>eng</language><publisher>Cary, NC: Oxford University Press</publisher><subject>Biological and medical sciences ; Cancer ; Cell Proliferation ; Cellular Senescence ; Confounding Factors, Epidemiologic ; Disease Progression ; DNA-Binding Proteins - deficiency ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Fibroblasts - metabolism ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Medical sciences ; Nuclear Proteins - deficiency ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; Oncology ; Prognosis ; Proteins ; Real-Time Polymerase Chain Reaction ; Research Design ; Retinoblastoma Protein - deficiency ; Retinoblastoma Protein - metabolism ; RNA, Complementary - metabolism ; Skin Neoplasms - chemically induced ; Skin Neoplasms - metabolism ; Tumors ; Ubiquitin-Protein Ligases ; Up-Regulation</subject><ispartof>JNCI : Journal of the National Cancer Institute, 2012-06, Vol.104 (12), p.941-952</ispartof><rights>2015 INIST-CNRS</rights><rights>Copyright Oxford Publishing Limited(England) Jun 20, 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c384t-77eef43975086aae37041e0f8e8039224c5b7ba5033b6b532215c2e5cb7208943</citedby><cites>FETCH-LOGICAL-c384t-77eef43975086aae37041e0f8e8039224c5b7ba5033b6b532215c2e5cb7208943</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27929,27930</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26136613$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22556269$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>ZOUMPOULIDOU, Georgia</creatorcontrib><creatorcontrib>BROCENO, Cristina</creatorcontrib><creatorcontrib>HE LI</creatorcontrib><creatorcontrib>BIRD, Demelza</creatorcontrib><creatorcontrib>THOMAS, George</creatorcontrib><creatorcontrib>MITTNACHT, Sibylle</creatorcontrib><title>Role of the Tripartite Motif Protein 27 in Cancer Development</title><title>JNCI : Journal of the National Cancer Institute</title><addtitle>J Natl Cancer Inst</addtitle><description>The tripartite motif family protein 27 (TRIM27) is a transcriptional repressor that interacts with, and attenuates senescence induction by, the retinoblastoma-associated protein (RB1). High expression of TRIM27 was noted in several human cancer types including breast and endometrial cancer, where elevated TRIM27 expression predicts poor prognosis. Here, we investigated the role of TRIM27 expression in cancer development.
We assessed TRIM27 expression in human cancer using cancer profiling arrays containing paired tumor and normal cRNA (n = 261) as well as in murine skin cancer induced by 7, 12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA). We generated mice with disrupted expression of murine TRIM27 (Trim27(-/-)) and assessed their susceptibility to DMBA/TPA-induced skin tumor development compared with isogenic littermates (n = 26 mice per group). We assessed the effect of Trim27 loss on senescence propensity in mouse embryonic fibroblasts (MEFs) by quantifying cell proliferation alongside senescence markers (senescence-associated β-galactosidase [SA-β-gal] activity and hypertrophic cell morphology). The contribution of RB1 on senescence and cancer susceptibility (n > 20 mice per group) in Trim27(-/-) backgrounds was also assessed. Data were analyzed using the Student's t, χ(2), or log-rank test as indicated. All statistical tests were two-sided.
TRIM27 transcript levels are statistically significantly increased in common human cancers, including colon and lung, vs normal tissues (TRIM27 expression relative to ubiquitin: cancers vs normal tissues, mean = 0.59, 95% confidence interval [CI] = 0.55 to 0.63 vs mean = 0.46, 95% CI =0.43 to 0.49, P < .001) as well as in chemically induced mouse skin cancer compared with matched normal tissue (Trim27 expression relative to Gapdh control: tumor vs normal skin, mean = 4.2, 95% CI = 3.97 to 4.43 vs mean = 0.96, 95% CI = 0.69 to 1.2, P < .001). Trim27(-/-) mice (n = 14) were resistant to chemically induced skin cancer development (eight [57.2%] of 14 mice were tumor free) compared with Trim27(+/+) wild-type littermates (n = 13) (one [7.7%] of 13 mice was tumor free). Trim27(-/-) MEFs show enhanced senescence propensity in response to replicative (percentage of SA-β-gal-positive cells: Trim27(+/+) MEFs vs Trim27(-/-) MEFs, mean = 14.2%, 95% CI = 11.1% to 17.4% vs mean = 53.3%, 95% CI = 48.7% to 57.9%, P < .001) or oncogenic stress (percentage of SA-β-gal-positive cells: Trim27(+/+) MEFs + Ras vs Trim27(-/-) MEFs + Ras, mean = 24.0%, 95% CI = 19.9% to 28.1% vs mean = 37.3%, 95% CI = 32.2% to 42.4%, P < .05) compared with Trim27(+/+) MEFs. These responses were alleviated following inactivation of murine RB1 (Rb1). Furthermore, Trim27(-/-) mice are not protected from cancers arising as a consequence of Rb1 deletion (median survival: Trim27(-/-)Rb(+/-) vs Trim27(+/+)Rb(+/-), 14 vs 13 months; difference = 1.0 month, 95% CI = 0.5 to 1.6 months, P = .14).
TRIM27 expression is a modifier of disease incidence and progression relevant to the development of common human cancers and is a potential target for intervention in cancer.</description><subject>Biological and medical sciences</subject><subject>Cancer</subject><subject>Cell Proliferation</subject><subject>Cellular Senescence</subject><subject>Confounding Factors, Epidemiologic</subject><subject>Disease Progression</subject><subject>DNA-Binding Proteins - deficiency</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Fibroblasts - metabolism</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Nuclear Proteins - deficiency</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>Oncology</subject><subject>Prognosis</subject><subject>Proteins</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Research Design</subject><subject>Retinoblastoma Protein - deficiency</subject><subject>Retinoblastoma Protein - metabolism</subject><subject>RNA, Complementary - metabolism</subject><subject>Skin Neoplasms - chemically induced</subject><subject>Skin Neoplasms - metabolism</subject><subject>Tumors</subject><subject>Ubiquitin-Protein Ligases</subject><subject>Up-Regulation</subject><issn>0027-8874</issn><issn>1460-2105</issn><issn>1460-2105</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpd0E1LwzAYwPEgipvTk3cpiCBIXV6b9OBB5itMFJnnkmZPsaVtatIKfntTNhUMJLn8eHj4I3RM8CXBKZtXrSnn68pTynfQlPAEx5RgsYumGFMZKyX5BB14X-FwUsr30YRSIRKapFN09WpriGwR9e8QrVzZadeXPURPti-L6MXZHso2ojIK70K3Blx0A59Q266Btj9Ee4WuPRxt_xl6u7tdLR7i5fP94-J6GRumeB9LCVBwlkqBVaI1MIk5AVwoUJilYW8jcplrgRnLk1wwSokwFITJJcUq5WyGzjdzO2c_BvB91pTeQF3rFuzgM4Ip4QInKg309B-t7ODasN2opFAhyqguNso4672DIutc2Wj3FVA2Vs3GqtmmatAn25lD3sD61_5kDOBsC7Q3ui5cKFX6P5cQloTLvgFE3n0k</recordid><startdate>20120620</startdate><enddate>20120620</enddate><creator>ZOUMPOULIDOU, Georgia</creator><creator>BROCENO, Cristina</creator><creator>HE LI</creator><creator>BIRD, Demelza</creator><creator>THOMAS, George</creator><creator>MITTNACHT, Sibylle</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>IQODW</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>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20120620</creationdate><title>Role of the Tripartite Motif Protein 27 in Cancer Development</title><author>ZOUMPOULIDOU, Georgia ; BROCENO, Cristina ; HE LI ; BIRD, Demelza ; THOMAS, George ; MITTNACHT, Sibylle</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c384t-77eef43975086aae37041e0f8e8039224c5b7ba5033b6b532215c2e5cb7208943</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Biological and medical sciences</topic><topic>Cancer</topic><topic>Cell Proliferation</topic><topic>Cellular Senescence</topic><topic>Confounding Factors, Epidemiologic</topic><topic>Disease Progression</topic><topic>DNA-Binding Proteins - deficiency</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Fibroblasts - metabolism</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Nuclear Proteins - deficiency</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>Oncology</topic><topic>Prognosis</topic><topic>Proteins</topic><topic>Real-Time Polymerase Chain Reaction</topic><topic>Research Design</topic><topic>Retinoblastoma Protein - deficiency</topic><topic>Retinoblastoma Protein - metabolism</topic><topic>RNA, Complementary - metabolism</topic><topic>Skin Neoplasms - chemically induced</topic><topic>Skin Neoplasms - metabolism</topic><topic>Tumors</topic><topic>Ubiquitin-Protein Ligases</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>ZOUMPOULIDOU, Georgia</creatorcontrib><creatorcontrib>BROCENO, Cristina</creatorcontrib><creatorcontrib>HE LI</creatorcontrib><creatorcontrib>BIRD, Demelza</creatorcontrib><creatorcontrib>THOMAS, George</creatorcontrib><creatorcontrib>MITTNACHT, Sibylle</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>JNCI : Journal of the National Cancer Institute</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>ZOUMPOULIDOU, Georgia</au><au>BROCENO, Cristina</au><au>HE LI</au><au>BIRD, Demelza</au><au>THOMAS, George</au><au>MITTNACHT, Sibylle</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role of the Tripartite Motif Protein 27 in Cancer Development</atitle><jtitle>JNCI : Journal of the National Cancer Institute</jtitle><addtitle>J Natl Cancer Inst</addtitle><date>2012-06-20</date><risdate>2012</risdate><volume>104</volume><issue>12</issue><spage>941</spage><epage>952</epage><pages>941-952</pages><issn>0027-8874</issn><issn>1460-2105</issn><eissn>1460-2105</eissn><coden>JNCIEQ</coden><abstract>The tripartite motif family protein 27 (TRIM27) is a transcriptional repressor that interacts with, and attenuates senescence induction by, the retinoblastoma-associated protein (RB1). High expression of TRIM27 was noted in several human cancer types including breast and endometrial cancer, where elevated TRIM27 expression predicts poor prognosis. Here, we investigated the role of TRIM27 expression in cancer development.
We assessed TRIM27 expression in human cancer using cancer profiling arrays containing paired tumor and normal cRNA (n = 261) as well as in murine skin cancer induced by 7, 12-dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA). We generated mice with disrupted expression of murine TRIM27 (Trim27(-/-)) and assessed their susceptibility to DMBA/TPA-induced skin tumor development compared with isogenic littermates (n = 26 mice per group). We assessed the effect of Trim27 loss on senescence propensity in mouse embryonic fibroblasts (MEFs) by quantifying cell proliferation alongside senescence markers (senescence-associated β-galactosidase [SA-β-gal] activity and hypertrophic cell morphology). The contribution of RB1 on senescence and cancer susceptibility (n > 20 mice per group) in Trim27(-/-) backgrounds was also assessed. Data were analyzed using the Student's t, χ(2), or log-rank test as indicated. All statistical tests were two-sided.
TRIM27 transcript levels are statistically significantly increased in common human cancers, including colon and lung, vs normal tissues (TRIM27 expression relative to ubiquitin: cancers vs normal tissues, mean = 0.59, 95% confidence interval [CI] = 0.55 to 0.63 vs mean = 0.46, 95% CI =0.43 to 0.49, P < .001) as well as in chemically induced mouse skin cancer compared with matched normal tissue (Trim27 expression relative to Gapdh control: tumor vs normal skin, mean = 4.2, 95% CI = 3.97 to 4.43 vs mean = 0.96, 95% CI = 0.69 to 1.2, P < .001). Trim27(-/-) mice (n = 14) were resistant to chemically induced skin cancer development (eight [57.2%] of 14 mice were tumor free) compared with Trim27(+/+) wild-type littermates (n = 13) (one [7.7%] of 13 mice was tumor free). Trim27(-/-) MEFs show enhanced senescence propensity in response to replicative (percentage of SA-β-gal-positive cells: Trim27(+/+) MEFs vs Trim27(-/-) MEFs, mean = 14.2%, 95% CI = 11.1% to 17.4% vs mean = 53.3%, 95% CI = 48.7% to 57.9%, P < .001) or oncogenic stress (percentage of SA-β-gal-positive cells: Trim27(+/+) MEFs + Ras vs Trim27(-/-) MEFs + Ras, mean = 24.0%, 95% CI = 19.9% to 28.1% vs mean = 37.3%, 95% CI = 32.2% to 42.4%, P < .05) compared with Trim27(+/+) MEFs. These responses were alleviated following inactivation of murine RB1 (Rb1). Furthermore, Trim27(-/-) mice are not protected from cancers arising as a consequence of Rb1 deletion (median survival: Trim27(-/-)Rb(+/-) vs Trim27(+/+)Rb(+/-), 14 vs 13 months; difference = 1.0 month, 95% CI = 0.5 to 1.6 months, P = .14).
TRIM27 expression is a modifier of disease incidence and progression relevant to the development of common human cancers and is a potential target for intervention in cancer.</abstract><cop>Cary, NC</cop><pub>Oxford University Press</pub><pmid>22556269</pmid><doi>10.1093/jnci/djs224</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Biological and medical sciences Cancer Cell Proliferation Cellular Senescence Confounding Factors, Epidemiologic Disease Progression DNA-Binding Proteins - deficiency DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Fibroblasts - metabolism Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Medical sciences Nuclear Proteins - deficiency Nuclear Proteins - genetics Nuclear Proteins - metabolism Oncology Prognosis Proteins Real-Time Polymerase Chain Reaction Research Design Retinoblastoma Protein - deficiency Retinoblastoma Protein - metabolism RNA, Complementary - metabolism Skin Neoplasms - chemically induced Skin Neoplasms - metabolism Tumors Ubiquitin-Protein Ligases Up-Regulation |
| title | Role of the Tripartite Motif Protein 27 in Cancer Development |
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