{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T10:13:59Z","timestamp":1789208039148,"version":"build-2803163510"},"reference-count":44,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2013,4,8]],"date-time":"2013-04-08T00:00:00Z","timestamp":1365379200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR052511"],"award-info":[{"award-number":["AR052511"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:p>\n                    The N\u2010end rule pathway contributes significantly to accelerated muscle proteolysis mediated by the ubiquitin\u2010proteasome pathway in various catabolic conditions. UBR2 (aka E3\u03b1\u2010II) is the only known E3 ubiquitin ligase of the N\u2010end rule pathway that is up\u2010regulated by cachectic stimuli including proinflammatory cytokines and tumors. However, the signaling mechanism through which UBR2 is up\u2010regulated remains undetermined. Here we identify a signaling pathway that mediates tumor cell\u2010induced up\u2010regulation of UBR2. UBR2 expression in C2C12 myotubes was up\u2010regulated by conditioned medium from Lewis lung carcinoma cells or C26 colon adenocarcinoma cells, which was blocked by a pharmacological inhibitor of p38\u03b1\/\u03b2 mitogen\u2010activated protein kinase (MAPK), SB202190. Similarly, SB202190 administration (i.p.) abolished UBR2 up\u2010regulation in the tibialis anterior of LLC tumor\u2010bearing mice. Genetic gain and loss of function assays in C2C12 myotubes indicated that tumor\u2010induced activation of the p38\u03b2 isoform is sufficient and necessary for UBR2 up\u2010regulation. In addition, UBR2 up\u2010regulation required p38\u03b2\u2010mediated phosphorylation of CCAAT\/enhancer binding protein (C\/EBP)\u2010\u03b2 Thr\u2010188, which was critical to C\/EBP\u03b2 binding to the\n                    <jats:italic>UBR2<\/jats:italic>\n                    promoter. Furthermore, luciferase reporter assay revealed that the C\/EBP\u03b2 binding motif in the\n                    <jats:italic>UBR2<\/jats:italic>\n                    promoter is a functional C\/EBP\u03b2\u2010responsive\n                    <jats:italic>cis<\/jats:italic>\n                    \u2010element that enhances the promoter activity on activation by p38\u03b2. Finally, genetic ablation of C\/EBP\u03b2 blocked UBR2 up\u2010regulation in LLC tumor\u2010bearing mice. These results suggest that UBR2 up\u2010regulation in cachectic muscle is mediated by the p38\u03b2\u2010C\/EBP\u03b2 signaling pathway responsible for the bulk of tumor\u2010induced muscle proteolysis.\u2014Zhang, G., Lin, R.\u2010K., Kwon, Y. T., Li, Y.\u2010P. Signaling mechanism of tumor cell\u2010induced up\u2010regulation of E3 ubiquitin ligase UBR2.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    27, 2893\u20132901 (2013).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.12-222711","type":"journal-article","created":{"date-parts":[[2013,4,8]],"date-time":"2013-04-08T22:02:24Z","timestamp":1365458544000},"page":"2893-2901","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Signaling mechanism of tumor cell\u2010induced up\u2010regulation of E3 ubiquitin ligase UBR2"],"prefix":"10.1096","volume":"27","author":[{"given":"Guohua","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Integrative Biology and Pharmacology University of Texas Health Science Center Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u2010Kuo","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology and Pharmacology University of Texas Health Science Center Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Tae","family":"Kwon","sequence":"additional","affiliation":[{"name":"Center for Pharmacogenetics University of Pittsburgh Pittsburgh Pennsylvania USA"},{"name":"Department of Pharmaceutical Sciences School of Pharmacy University of Pittsburgh Pittsburgh Pennsylvania USA"},{"name":"World Class University Program Department of Molecular Medicine and Biopharmaceutical Sciences Graduate School of Convergence Science and Technology and College of Medicine Seoul National University Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010Ping","family":"Li","sequence":"additional","affiliation":[{"name":"Department of 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