Fbxo25 controls Tbx5 and Nkx2-5 transcriptional activity to regulate cardiomyocyte development

Biochimica Et Biophysica Acta
Hoe-Su JeongKye-Seong Kim

Abstract

The 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, Fbxo251-236, 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, w...Continue Reading

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Citations

Sep 7, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Gui-Yang JiangYong Zhang
Dec 19, 2019·Journal of Child Psychology and Psychiatry, and Allied Disciplines·Benjamin HarichBarbara Franke
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Oct 30, 2020·International Journal of Molecular Sciences·Jordan BlondelleStephan Lange
Sep 8, 2021·American Journal of Medical Genetics. Part a·De-Gang WangTian-Hua Huang

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