{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T23:01:32Z","timestamp":1715986892837},"reference-count":35,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2006,2,22]],"date-time":"2006-02-22T00:00:00Z","timestamp":1140566400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecular Carcinogenesis"],"published-print":{"date-parts":[[2006,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Several studies have shown that HER\u20102\/neu (erbB\u20102) blocking therapy strategies can cause tumor remission. However, the responsible molecular mechanisms are not yet known. Both ERK1\/2 and Akt\/PKB are critical for HER\u20102\u2010mediated signal transduction. Therefore, we used a mouse tumor model that allows downregulation of HER\u20102 in tumor tissue by administration of anhydrotetracycline (ATc). Switching\u2010off HER\u20102 caused a rapid tumor remission by more than 95% within 7 d of ATc administration compared to the volume before switching\u2010off HER\u20102. Interestingly, HER\u20102 downregulation caused a dephosphorylation of p\u2010ERK1\/2 by more than 80% already before tumor remission occurred. Levels of total ERK protein were not influenced. In contrast, dephosphorylation of p\u2010Akt occurred later, when the tumor was already in remission. These data suggest that in our HER\u20102 tumor model dephosphorylation of p\u2010ERK1\/2 may be more critical for tumor remission than dephosphorylation of p\u2010Akt. To test this hypothesis we used a second mouse tumor model that allows ATc controlled expression of BXB\u2010Raf1 because the latter constitutively signals to ERK1\/2, but cannot activate Akt\/PKB. As expected, downregulation of BXB\u2010Raf1 in tumor tissue caused a strong dephosphorylation of p\u2010ERK1\/2, but did not decrease levels of p\u2010Akt. Interestingly, tumor remission after switching\u2010off BXB\u2010Raf1 was similarly efficient as the effect of HER\u20102 downregulation, despite the lack of p\u2010Akt dephosphorylation. In conclusion, two lines of evidence strongly suggest that dephosphorylation of p\u2010ERK1\/2 and not that of p\u2010Akt is critical for the rapid tumor remission after downregulation of HER\u20102 or BXB\u2010Raf1 in our tumor model: (i) dephosphorylation of p\u2010ERK1\/2 but not that of p\u2010Akt precedes tumor remission after switching\u2010off HER\u20102 and (ii) downregulation of BXB\u2010Raf1 leads to a similarly efficient tumor remission as downregulation of HER\u20102, although no p\u2010Akt dephosphorylation was observed after switching\u2010off BXB\u2010Raf1. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/mc.20157","type":"journal-article","created":{"date-parts":[[2006,2,22]],"date-time":"2006-02-22T22:47:14Z","timestamp":1140648434000},"page":"302-308","source":"Crossref","is-referenced-by-count":11,"title":["Dephosphorylation of p\u2010ERK1\/2 in relation to tumor remission after HER\u20102 and Raf1 blocking therapy in a conditional mouse tumor model"],"prefix":"10.1002","volume":"45","author":[{"given":"Carolin K.","family":"Hausherr","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilka B.","family":"Schiffer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Gebhard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Bani\u0107","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Berno","family":"Tanner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heinz","family":"Kolbl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Thoenes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Beckers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Spangenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Prawitt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatjana","family":"Trost","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernhard","family":"Zabel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franz","family":"Oesch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Hermes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan G.","family":"Hengstler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2006,2,22]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7792603"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.08.187"},{"key":"e_1_2_7_4_2","first-page":"563","article-title":"Switching off HER\u20102 expression leads to apoptosis and complete remission of tumors in nude mice","volume":"365","author":"Schiffer IB","year":"2002","journal-title":"Naunyn Schmiedebergs Arch Pharmacol"},{"key":"e_1_2_7_5_2","first-page":"7221","article-title":"Switching off HER\u20102\/neu in a tetracycline controlled mouse tumor model leads to apoptosis and tumor\u2010size dependent remission","volume":"63","author":"Schiffer IB","year":"2003","journal-title":"Cancer Res"},{"key":"e_1_2_7_6_2","first-page":"901","article-title":"Reversible tumorgenesis in mice by conditional expression of the HER2\/c\u2010erbB2 receptor tyrosine kinase","volume":"13","author":"Baasner S","year":"1996","journal-title":"Oncogene"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(02)00212-X"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)00114-8"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/19.13.3159"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-4827(02)00101-5"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.10109"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111974200"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072682"},{"key":"e_1_2_7_14_2","unstructured":"BeckersT ThoenesE AppH HilgardP.Inducible tumorigenic signalling by conditional expression of oncogenic raf and ras proteins. 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