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dc.contributor.author김계성-
dc.date.accessioned2017-03-06T02:24:19Z-
dc.date.available2017-03-06T02:24:19Z-
dc.date.issued2015-06-
dc.identifier.citationBIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS, v. 1849, NO 6, Page. 709-721en_US
dc.identifier.issn1874-9399-
dc.identifier.issn0006-3002-
dc.identifier.urihttp://www.sciencedirect.com/science/article/pii/S1874939915000504-
dc.identifier.urihttp://hdl.handle.net/20.500.11754/25851-
dc.description.abstractThe ubiquitin-proteasome system (UPS) plays an important role in protein quality control, cellular signalings, and cell differentiation through the regulated turnover of key transcription factors in cardiac tissue. However, the molecular mechanism underlying Fbxo25-mediated ubiquitination of cardiac transcription factors remains elusive. We report that an Fbxo25-mediated SCF ubiquitination pathway regulates the protein levels and activities of Tbx5 and Nkx2-5 based on our studies using MG132, proteasome inhibitor, and the temperature sensitive ubiquitin system in ts20 cells. Our data indicate that Fbxo25 directly interacts with Tbx5 and Nkx2-5 in vitro and in vivo. In support of our findings, a dominant-negative mutant of Fbxo25, Fbxo25(1-236), prevents Tbx5 degradation and increases Tbx5 transcriptional activity in a Tbx5 responsive luciferase assay. Therefore, Fbxo25 facilitates Tbx5 degradation in an SCF-dependent manner. In addition, the silencing of endogenous Fbxo25 increases Tbx5 and Nkx2-5 mRNA levels and suppresses mESC-derived cardiomyocyte differentiation. Likewise, the exogenous expression of FBXO25 downregulates NKX2-5 level in human ESC-derived cardiomyocytes. In myocardial infarction model, Fbxo25 mRNA decreases, whereas the mRNA and protein levels of Tbx5 and Nkx2-5 increase. The protein levels of Tbx5 and Nkx2-5 are regulated negatively by Fbxo25-mediated SCF ubiquitination pathway. Thus, our findings reveal a novel mechanism for regulation of SCFFbox25-dependent Nkx2-5 and Tbx5 ubiquitination in cardiac development and provide a new insight into the regulatory mechanism of Nkx2-5 and Tbx5 transcriptional activity. (C) 2015 Elsevier B.V. All rights reserved.en_US
dc.description.sponsorshipThis research was supported in part by the Korea Health Technology R&D Project, Ministry of Health & Welfare (A120262), the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (No. 2012M3A9B4028738).en_US
dc.language.isoenen_US
dc.publisherELSEVIER SCIENCE BVen_US
dc.subjectFbxo25en_US
dc.subjectTbx5en_US
dc.subjectNkx2-5en_US
dc.subjectE3 ubiquitin ligaseen_US
dc.subjectCardiomyocyteen_US
dc.titleFbxo25 controls Tbx5 and Nkx2-5 transcriptional activity to regulate cardiomyocyte developmenten_US
dc.typeArticleen_US
dc.relation.no6-
dc.relation.volume1849-
dc.identifier.doi10.1016/j.bbagrm.2015.02.002-
dc.relation.page709-721-
dc.relation.journalBIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS-
dc.contributor.googleauthorJeong, Hoe-Su-
dc.contributor.googleauthorJung, Eun-Shil-
dc.contributor.googleauthorSim, Ye-Ji-
dc.contributor.googleauthorKim, Su-Jin-
dc.contributor.googleauthorJang, Jae-Woo-
dc.contributor.googleauthorHong, Ki-Sung-
dc.contributor.googleauthorLee, Won-Young-
dc.contributor.googleauthorChung, Hyung-Min-
dc.contributor.googleauthorPark, Kyung-Tae-
dc.contributor.googleauthorKim, Kye-Seong-
dc.relation.code2015000450-
dc.sector.campusS-
dc.sector.daehakCOLLEGE OF MEDICINE[S]-
dc.sector.departmentDEPARTMENT OF MEDICINE-
dc.identifier.pidks66kim-
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COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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