{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T11:31:31Z","timestamp":1790422291880,"version":"4.1.0"},"reference-count":35,"publisher":"The Endocrine Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,1,1]]},"abstract":"<jats:p>Context: The oncogenic BRAFV600E mutation results in an active structural conformation characterized by greatly elevated ERK activity. However, additional cellular effects caused by subcellular action of BRAFV600E remain to be identified.<\/jats:p>\n               <jats:p>Objective: To explore these effects, differences in the subcellular localization of wild-type and mutant BRAF in thyroid cancer were investigated.<\/jats:p>\n               <jats:p>Results: A significant proportion of endogenous and exogenous BRAFV600E, but not wild-type BRAF, was detected in the mitochondrial fraction, similar to other BRAF mutants including BRAFV600D, BRAFV600K, BRAFV600R, and BRAFG469A, which showed elevated kinase activity and mitochondrial localization. Induced expression of BRAFV600E suppressed the apoptotic responses against staurosporine and TNF\u03b1\/cycloheximide. Interestingly, the mitochondrial localization and antiapoptotic activities of BRAFV600E were unaffected by sorafenib and U0126 suppression of MAPK kinase (MEK) and ERK activities. Similarly, although the RAF inhibitor sorafenib effectively inhibited MEK\/ERK activation, it did not block the mitochondrial localization of BRAFV600E. In addition, inducible expression of BRAFV600E increased the glucose uptake rate and decreased O2 consumption, suggesting that BRAFV600E reduces mitochondrial oxidative phosphorylation, a signature feature of cancer cells. Again, these metabolic alterations resulted by BRAFV600E expression were not affected by the treatment of thyroid cells by sorafenib. Therefore, RAF and MEK inhibitors are unable to block the antiapoptotic activity of BRAFV600E or correct the high glucose uptake rate and glycolytic activity and suppressed mitochondrial oxidative phosphorylation induced by BRAFV600E.<\/jats:p>\n               <jats:p>Conclusions: The mitochondrial localization observed in oncogenic BRAF mutants might be related to their altered responses to apoptotic stimuli and characteristic metabolic phenotypes found in thyroid cancer. The inability of MEK and RAF inhibitors, U0126 and sorafenib, respectively, to block the mitochondrial localization of BRAFV600E has additional therapeutic implications for BRAFV600E-positive thyroid cancers.<\/jats:p>","DOI":"10.1210\/jc.2010-1071","type":"journal-article","created":{"date-parts":[[2010,10,7]],"date-time":"2010-10-07T01:37:02Z","timestamp":1286415422000},"page":"E19-E30","source":"Crossref","is-referenced-by-count":54,"title":["Mitochondrial Localization and Regulation of BRAFV600E in Thyroid Cancer: A Clinically Used RAF Inhibitor Is Unable to Block the Mitochondrial Activities of BRAFV600E"],"prefix":"10.1210","volume":"96","author":[{"given":"Min Hee","family":"Lee","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine (M.H.L., S.E.L., D.W.K., M.J.R., S.Jin.K., S.Joong.K., Y.K.K., Y.S.J., M.S.), Laboratory of Endocrine Cell Biology, Division of Endocrinology, Chungnam National University School of Medicine, Jung-gu Daejeon 301-721, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Eun","family":"Lee","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine (M.H.L., S.E.L., D.W.K., M.J.R., S.Jin.K., S.Joong.K., Y.K.K., Y.S.J., M.S.), Laboratory of Endocrine Cell Biology, Division of Endocrinology, Chungnam National University School of Medicine, Jung-gu Daejeon 301-721, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Wook","family":"Kim","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine (M.H.L., S.E.L., D.W.K., M.J.R., S.Jin.K., S.Joong.K., Y.K.K., Y.S.J., M.S.), Laboratory of Endocrine Cell Biology, Division of Endocrinology, Chungnam National University School of Medicine, Jung-gu Daejeon 301-721, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Jeong","family":"Ryu","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine (M.H.L., S.E.L., D.W.K., M.J.R., 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Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Kyoung","family":"Kim","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine (M.H.L., S.E.L., D.W.K., M.J.R., S.Jin.K., S.Joong.K., Y.K.K., Y.S.J., M.S.), Laboratory of Endocrine Cell Biology, Division of Endocrinology, Chungnam National University School of Medicine, Jung-gu Daejeon 301-721, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hoon","family":"Park","sequence":"additional","affiliation":[{"name":"Biochemistry (J.H.P., G.R.K.), Laboratory of Endocrine Cell Biology, Division of Endocrinology, Chungnam National University School of Medicine, Jung-gu Daejeon 301-721, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gi Ryang","family":"Kweon","sequence":"additional","affiliation":[{"name":"Biochemistry (J.H.P., G.R.K.), Laboratory of Endocrine Cell Biology, Division of Endocrinology, Chungnam National University School of Medicine, Jung-gu Daejeon 301-721, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Man","family":"Kim","sequence":"additional","affiliation":[{"name":"Pathology (J.M.K.), Laboratory of Endocrine Cell Biology, Division of Endocrinology, Chungnam National University School of Medicine, Jung-gu Daejeon 301-721, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Uee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pathology (J.U.L.), Daejeon St. Mary\u2019s Hospital, The Catholic University of Korea, Jung-gu Daejeon 301-723, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"De Falco","sequence":"additional","affiliation":[{"name":"Dipartimento di Biologia e Patologia Cellulare e Molecolare (V.D.F.), Universita\u0301 Federico II\/Istituto di Endocrinologia e Oncologia Sperimentale Consiglio Nazionale delle Ricerche, 80131 Napoli, 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