Erythropoietin Prevents Hypoxia-Induced GATA-4 Ubiquitination via Phosphorylation of Serine 105 of GATA-4
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概要
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Erythropoietin (EPO), an essential hormone for erythropoiesis, can provide protection against myocardial ischemia/reperfusion (I/R) injury and hypoxic apoptosis. GATA-4 is a zinc finger transcription factor, and its activation and post-translational modification are essential components in the transcriptional response to hypoxia. GATA-4 has also been reported to play a role in the cellular mechanisms of EPO-induced myocardial protection against I/R injury. In this study, we aimed to investigate the influence of EPO on GATA-4 protein stability and post-translational modification under hypoxic conditions without reperfusion. EPO induced cell viability under long-term hypoxia. EPO significantly increased phosphorylation of GATA-4 via the extracellular signal-regulated kinase (ERK) signaling pathway and reduced hypoxia-induced GATA-4 ubiquitination, which enhanced GATA-4 stability under hypoxia. ERK activation by over-expression of constitutively active mitogen-activated protein kinase 1 (MEK1) strongly increased GATA-4 phosphorylation and its protein levels and decreased GATA-4 ubiquitination under hypoxia. Despite ERK activation, GATA-4 ubiquitination was not affected under hypoxia in a GATA-4-S105A mutant. Under hypoxic condition without reperfusion, EPO-induced ERK activation was associated with post-translational modification of GATA-4, mediated by enhancement of phosphorylation of GATA-4 at Ser-105. Subsequent attenuation of GATA-4 ubiquitination led to increases in GATA-4 protein stability, which resulted in increased cell viability under hypoxia.
著者
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Kim Si
Department of Anesthesiology and Pain Medicine, College of Medicine, Kyungpook National University Hospital
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Jun Ji
Severance Biomedical Science Institute, Yonsei University College of Medicine
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Shin Eun
Anesthesia and Pain Research Institute, Yonsei University Health System
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Kim Ji
Anesthesia and Pain Research Institute, Yonsei University Health System
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Shim Jae-Kwang
Anesthesia and Pain Research Institute, Yonsei University Health System
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Kwak Young-Lan
Severance Biomedical Science Institute, Yonsei University College of Medicine
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- Erythropoietin Prevents Hypoxia-Induced GATA-4 Ubiquitination via Phosphorylation of Serine 105 of GATA-4