{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T09:20:10Z","timestamp":1759742410136,"version":"3.37.3"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,10,1]],"date-time":"2020-10-01T00:00:00Z","timestamp":1601510400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,1]],"date-time":"2020-10-01T00:00:00Z","timestamp":1601510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001513","name":"Cancer Society of New Zealand","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001513","id-type":"DOI","asserted-by":"publisher"}]},{"name":"DSM Dean's Bequest Fund"},{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The tumour suppressor gene, <jats:italic>TES<\/jats:italic>, is frequently methylated in many human tumours. Previously, we demonstrated that <jats:italic>TES<\/jats:italic> promoter methylation and transcriptional silencing was the most common molecular abnormality detected in childhood acute lymphoblastic leukaemia (ALL). <jats:italic>Trp53<\/jats:italic>-mutant mouse models predominantly develop B- and T-cell lymphomas, which are widely considered equivalent to childhood T and B ALL. In this study, we examined expression of <jats:italic>Tes<\/jats:italic> transcript and Testin protein in spontaneous tumours obtained from three <jats:italic>Trp53<\/jats:italic>-mutant mouse models. Using immunohistochemistry, we report that 47% of lymphomas lacked Testin protein compared to only 7% of non-lymphoid tumours. Further examination of the lymphomas from <jats:italic>Trp53-null<\/jats:italic> and <jats:italic>Trp53-m\u0394pro<\/jats:italic> homozygous mutant mice revealed that 63% and 69% respectively of the isolated lymphomas were Testin negative, which is similar to reported rates in childhood T-ALL. Surprisingly, lymphomas from <jats:italic>Trp53-\u0394122<\/jats:italic> mice were frequently Testin positive (&gt;\u200960%), suggesting that the presence of the Trp53-\u0394122 protein appeared to mitigate the requirement for <jats:italic>Tes<\/jats:italic> silencing in lymphomagenesis. Quantitative RT-PCR results confirmed that this lack of Testin protein was due to <jats:italic>Tes<\/jats:italic> transcriptional silencing, although bisulfite sequencing demonstrated that this was not due to promoter methylation. These results are consistent with the Testin protein having lymphoid tumour suppressor activity in both mice and humans.<\/jats:p>","DOI":"10.1038\/s41598-020-73229-3","type":"journal-article","created":{"date-parts":[[2020,10,1]],"date-time":"2020-10-01T10:04:13Z","timestamp":1601546653000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Silencing of Testin expression is a frequent event in spontaneous lymphomas from Trp53-mutant mice"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0474-9089","authenticated-orcid":false,"given":"Robert J.","family":"Weeks","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jackie L.","family":"Ludgate","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gwenn","family":"Le M\u00e9e","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rubina","family":"Khanal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunali","family":"Mehta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gail","family":"Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tania L.","family":"Slatter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antony W.","family":"Braithwaite","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian M.","family":"Morison","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,10,1]]},"reference":[{"key":"73229_CR1","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s40001-014-0066-4","volume":"19","author":"Y Bai","year":"2014","unstructured":"Bai, Y., Zhang, Q. G. & Wang, X. H. Downregulation of TES by hypermethylation in glioblastoma reduces cell apoptosis and predicts poor clinical outcome. Eur. J. Med. Res. 19, 66. https:\/\/doi.org\/10.1186\/s40001-014-0066-4 (2014).","journal-title":"Eur. J. Med. Res."},{"key":"73229_CR2","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/sj.onc.1209805","volume":"26","author":"W Mueller","year":"2007","unstructured":"Mueller, W. et al. Downregulation of RUNX3 and TES by hypermethylation in glioblastoma. Oncogene 26, 583\u2013593. https:\/\/doi.org\/10.1038\/sj.onc.1209805 (2007).","journal-title":"Oncogene"},{"key":"73229_CR3","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1007\/s11060-013-1133-3","volume":"113","author":"D Skiriut\u0117","year":"2013","unstructured":"Skiriut\u0117, D. et al. Promoter methylation of AREG, HOXA11, hMLH1, NDRG2, NPTX2 and Tes genes in glioblastoma. J. Neurooncol. 113, 441\u2013449. https:\/\/doi.org\/10.1007\/s11060-013-1133-3 (2013).","journal-title":"J. Neurooncol."},{"key":"73229_CR4","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1186\/1476-4598-9-190","volume":"9","author":"H Ma","year":"2010","unstructured":"Ma, H. et al. Extensive analysis of D7S486 in primary gastric cancer supports TESTIN as a candidate tumor suppressor gene. Mol. Cancer 9, 190. https:\/\/doi.org\/10.1186\/1476-4598-9-190 (2010).","journal-title":"Mol. Cancer"},{"key":"73229_CR5","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1158\/1078-0432.806.11.2","volume":"11","author":"M Sarti","year":"2005","unstructured":"Sarti, M. et al. Adenoviral transduction of TESTIN gene into breast and uterine cancer cell lines promotes apoptosis and tumor reduction in vivo. Clin. Cancer Res. 11, 806\u2013813 (2005).","journal-title":"Clin. Cancer Res."},{"key":"73229_CR6","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.1111\/j.1349-7006.2010.01497.x","volume":"101","author":"H Qiu","year":"2010","unstructured":"Qiu, H. et al. Frequent hypermethylation and loss of heterozygosity of the testis derived transcript gene in ovarian cancer. Cancer Sci. 101, 1255\u20131260. https:\/\/doi.org\/10.1111\/j.1349-7006.2010.01497.x (2010).","journal-title":"Cancer Sci."},{"key":"73229_CR7","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1002\/ijc.20337","volume":"111","author":"L Chene","year":"2004","unstructured":"Chene, L. et al. Extensive analysis of the 7q31 region in human prostate tumors supports TES as the best candidate tumor suppressor gene. Int. J. Cancer 111, 798\u2013804. https:\/\/doi.org\/10.1002\/ijc.20337 (2004).","journal-title":"Int. J. Cancer"},{"key":"73229_CR8","doi-asserted-by":"publisher","first-page":"2092","DOI":"10.1111\/cas.12020","volume":"103","author":"J Zhu","year":"2012","unstructured":"Zhu, J. et al. Testin is a tumor suppressor and prognostic marker in breast cancer. Cancer Sci. 103, 2092\u20132101. https:\/\/doi.org\/10.1111\/cas.12020 (2012).","journal-title":"Cancer Sci."},{"key":"73229_CR9","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1186\/1476-4598-9-163","volume":"9","author":"RJ Weeks","year":"2010","unstructured":"Weeks, R. J., Kees, U. R., Song, S. & Morison, I. M. Silencing of TESTIN by dense biallelic promoter methylation is the most common molecular event in childhood acute lymphoblastic leukaemia. Mol. Cancer 9, 163. https:\/\/doi.org\/10.1186\/1476-4598-9-163 (2010).","journal-title":"Mol. Cancer"},{"key":"73229_CR10","doi-asserted-by":"publisher","first-page":"45819","DOI":"10.18632\/oncotarget.9961","volume":"7","author":"H Li","year":"2016","unstructured":"Li, H. et al. TES inhibits colorectal cancer progression through activation of p38. Oncotarget 7, 45819\u201345836. https:\/\/doi.org\/10.18632\/oncotarget.9961 (2016).","journal-title":"Oncotarget"},{"key":"73229_CR11","doi-asserted-by":"publisher","first-page":"e0151341","DOI":"10.1371\/journal.pone.0151341","volume":"11","author":"RJ Weeks","year":"2016","unstructured":"Weeks, R. J., Ludgate, J. L., LeMee, G. & Morison, I. M. TESTIN induces rapid death and suppresses proliferation in childhood B acute lymphoblastic leukaemia cells. PLoS\u00a0One 11, e0151341. https:\/\/doi.org\/10.1371\/journal.pone.0151341 (2016).","journal-title":"PLoS\u00a0One"},{"key":"73229_CR12","doi-asserted-by":"publisher","first-page":"980","DOI":"10.12659\/MSM.890544","volume":"20","author":"Z Gu","year":"2014","unstructured":"Gu, Z. et al. TESTIN suppresses tumor growth and invasion via manipulating cell cycle progression in endometrial carcinoma. Med. Sci. Monit. 20, 980\u2013987. https:\/\/doi.org\/10.12659\/MSM.890544 (2014).","journal-title":"Med. Sci. Monit."},{"key":"73229_CR13","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.3892\/or.2016.5316","volume":"37","author":"M Wang","year":"2017","unstructured":"Wang, M. et al. Testin is a tumor suppressor in non-small cell lung cancer. Oncol. Rep. 37, 1027\u20131035. https:\/\/doi.org\/10.3892\/or.2016.5316 (2017).","journal-title":"Oncol. Rep."},{"key":"73229_CR14","doi-asserted-by":"publisher","first-page":"2555","DOI":"10.7314\/apjcp.2015.16.6.2555","volume":"16","author":"Z Zhong","year":"2015","unstructured":"Zhong, Z., Zhang, F. & Yin, S.-C. Effects of TESTIN gene expression on proliferation and migration of the 5\u20138F nasopharyngeal carcinoma cell line. Asian Pac. J. Cancer Prev. 16, 2555\u20132559. https:\/\/doi.org\/10.7314\/apjcp.2015.16.6.2555 (2015).","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"73229_CR15","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1038\/nrc2723","volume":"9","author":"AJ Levine","year":"2009","unstructured":"Levine, A. J. & Oren, M. The first 30 years of p53: Growing ever more complex. Nat. Rev. Cancer 9, 749\u2013758. https:\/\/doi.org\/10.1038\/nrc2723 (2009).","journal-title":"Nat. Rev. Cancer"},{"key":"73229_CR16","doi-asserted-by":"publisher","first-page":"a001008","DOI":"10.1101\/cshperspect.a001008","volume":"2","author":"M Olivier","year":"2010","unstructured":"Olivier, M., Hollstein, M. & Hainaut, P. TP53 mutations in human cancers: Origins, consequences, and clinical use. Cold Spring Harb Perspect. Biol. 2, a001008. https:\/\/doi.org\/10.1101\/cshperspect.a001008 (2010).","journal-title":"Cold Spring Harb Perspect. Biol."},{"key":"73229_CR17","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/356215a0","volume":"356","author":"LA Donehower","year":"1992","unstructured":"Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215\u2013221. https:\/\/doi.org\/10.1038\/356215a0 (1992).","journal-title":"Nature"},{"key":"73229_CR18","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1038\/cdd.2009.136","volume":"17","author":"TL Slatter","year":"2010","unstructured":"Slatter, T. L. et al. p53-mediated apoptosis prevents the accumulation of progenitor B cells and B-cell tumors. Cell Death Differ. 17, 540\u2013550. https:\/\/doi.org\/10.1038\/cdd.2009.136 (2010).","journal-title":"Cell Death Differ."},{"key":"73229_CR19","doi-asserted-by":"publisher","first-page":"5166","DOI":"10.1182\/blood-2010-11-321851","volume":"117","author":"TL Slatter","year":"2011","unstructured":"Slatter, T. L. et al. Hyperproliferation, cancer, and inflammation in mice expressing a Delta133p53-like isoform. Blood 117, 5166\u20135177. https:\/\/doi.org\/10.1182\/blood-2010-11-321851 (2011).","journal-title":"Blood"},{"key":"73229_CR20","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1182\/blood.V100.1.246","volume":"100","author":"HC Morse","year":"2002","unstructured":"Morse, H. C. Bethesda proposals for classification of lymphoid neoplasms in mice. Blood 100, 246\u2013258. https:\/\/doi.org\/10.1182\/blood.V100.1.246 (2002).","journal-title":"Blood"},{"key":"73229_CR21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0960-9822(00)00002-6","volume":"4","author":"T Jacks","year":"1994","unstructured":"Jacks, T. et al. Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4, 1\u20137. https:\/\/doi.org\/10.1016\/s0960-9822(00)00002-6 (1994).","journal-title":"Curr. Biol."},{"key":"73229_CR22","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1101\/cshperspect.a026039","volume":"6","author":"SM Joruiz","year":"2016","unstructured":"Joruiz, S. M. & Bourdon, J. C. p53 isoforms: Key regulators of the cell fate decision. Cold Spring Harb. Perspect. Med. 6, 20. https:\/\/doi.org\/10.1101\/cshperspect.a026039 (2016).","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"73229_CR23","doi-asserted-by":"publisher","first-page":"e0116270","DOI":"10.1371\/journal.pone.0116270","volume":"10","author":"S Sawhney","year":"2015","unstructured":"Sawhney, S. et al. Alpha-enolase is upregulated on the cell surface and responds to plasminogen activation in mice expressing a 133p53alpha mimic. PLoS\u00a0One 10, e0116270. https:\/\/doi.org\/10.1371\/journal.pone.0116270 (2015).","journal-title":"PLoS\u00a0One"},{"key":"73229_CR24","doi-asserted-by":"publisher","first-page":"446","DOI":"10.4161\/cc.11.3.19054","volume":"11","author":"HG Campbell","year":"2012","unstructured":"Campbell, H. G. et al. Does Delta133p53 isoform trigger inflammation and autoimmunity?. Cell Cycle 11, 446\u2013450. https:\/\/doi.org\/10.4161\/cc.11.3.19054 (2012).","journal-title":"Cell Cycle"},{"key":"73229_CR25","doi-asserted-by":"publisher","first-page":"4981","DOI":"10.1038\/onc.2016.45","volume":"35","author":"I Roth","year":"2016","unstructured":"Roth, I. et al. The Delta133p53 isoform and its mouse analogue Delta122p53 promote invasion and metastasis involving pro-inflammatory molecules interleukin-6 and CCL2. Oncogene 35, 4981\u20134989. https:\/\/doi.org\/10.1038\/onc.2016.45 (2016).","journal-title":"Oncogene"},{"key":"73229_CR26","doi-asserted-by":"publisher","first-page":"774","DOI":"10.4236\/abb.2013.47101","volume":"04","author":"F Arumemi","year":"2013","unstructured":"Arumemi, F., Bayles, I., Paul, J. & Milcarek, C. Shared and discrete interacting partners of ELL1 and ELL2 by yeast two-hybrid assay. Adv. Biosci. Biotechnol. 04, 774\u2013780. https:\/\/doi.org\/10.4236\/abb.2013.47101 (2013).","journal-title":"Adv. Biosci. Biotechnol."},{"key":"73229_CR27","doi-asserted-by":"publisher","first-page":"4230","DOI":"10.1128\/mcb.23.12.4230-4246.2003","volume":"23","author":"D Wiederschain","year":"2003","unstructured":"Wiederschain, D., Kawai, H., Gu, J., Shilatifard, A. & Yuan, Z. M. Molecular basis of p53 functional inactivation by the leukemic protein MLL-ELL. Mol. Cell. Biol. 23, 4230\u20134246. https:\/\/doi.org\/10.1128\/mcb.23.12.4230-4246.2003 (2003).","journal-title":"Mol. Cell. Biol."},{"key":"73229_CR28","doi-asserted-by":"publisher","first-page":"e0140511","DOI":"10.1371\/journal.pone.0140511","volume":"10","author":"E Hadzic","year":"2015","unstructured":"Hadzic, E. et al. Delineating the tes interaction site in zyxin and studying cellular effects of its disruption. PLoS\u00a0One 10, e0140511. https:\/\/doi.org\/10.1371\/journal.pone.0140511 (2015).","journal-title":"PLoS\u00a0One"},{"key":"73229_CR29","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.1158\/0008-5472.CAN-10-3486","volume":"71","author":"J Crone","year":"2011","unstructured":"Crone, J. et al. Zyxin is a critical regulator of the apoptotic HIPK2-p53 signaling axis. Cancer Res. 71, 2350\u20132359. https:\/\/doi.org\/10.1158\/0008-5472.CAN-10-3486 (2011).","journal-title":"Cancer Res."},{"key":"73229_CR30","doi-asserted-by":"publisher","first-page":"29146","DOI":"10.18632\/oncotarget.25635","volume":"9","author":"SY Mehta","year":"2018","unstructured":"Mehta, S. Y. et al. Regulation of the interferon-gamma (IFN-gamma) pathway by p63 and Delta133p53 isoform in different breast cancer subtypes. Oncotarget 9, 29146\u201329161. https:\/\/doi.org\/10.18632\/oncotarget.25635 (2018).","journal-title":"Oncotarget"},{"issue":"Suppl 1","key":"73229_CR31","doi-asserted-by":"publisher","first-page":"S20","DOI":"10.1186\/1471-2105-8-S1-S20","volume":"8","author":"E Sbisa","year":"2007","unstructured":"Sbisa, E. et al. p53FamTaG: A database resource of human p53, p63 and p73 direct target genes combining in silico prediction and microarray data. BMC Bioinform. 8(Suppl 1), S20. https:\/\/doi.org\/10.1186\/1471-2105-8-S1-S20 (2007).","journal-title":"BMC Bioinform."},{"key":"73229_CR32","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1038\/nature05993","volume":"450","author":"W Hu","year":"2007","unstructured":"Hu, W., Feng, Z., Teresky, A. K. & Levine, A. J. p53 regulates maternal reproduction through LIF. Nature 450, 721\u2013724. https:\/\/doi.org\/10.1038\/nature05993 (2007).","journal-title":"Nature"},{"key":"73229_CR33","doi-asserted-by":"publisher","first-page":"3137","DOI":"10.1002\/dvdy.21338","volume":"236","author":"LA Crompton","year":"2007","unstructured":"Crompton, L. A., Du Roure, C. & Rodriguez, T. A. Early embryonic expression patterns of the mouse Flamingo and Prickle orthologues. Dev. Dyn. 236, 3137\u20133143. https:\/\/doi.org\/10.1002\/dvdy.21338 (2007).","journal-title":"Dev. Dyn."},{"key":"73229_CR34","first-page":"20","volume":"20","author":"JMT Gao","year":"2018","unstructured":"Gao, J. M. T. et al. The cbioportal for cancer genomics: An intuitive open-source platform for exploration, analysis and visualization of cancer genomics data. AACR 20, 20 (2018).","journal-title":"AACR"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-73229-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-73229-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-73229-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T20:02:10Z","timestamp":1670356930000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-73229-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,1]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["73229"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-73229-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2020,10,1]]},"assertion":[{"value":"4 December 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 September 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 October 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"16255"}}