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Erythropoietin Prevents Hypoxia-Induced GATA-4 Ubiquitination via Phosphorylation of Serine 105 of GATA-4

 Ji Hae Jun  ;  Eun Jung Shin  ;  Ji Ho Kim  ;  Si Oh Kim  ;  Jae-Kwang Shim  ;  Young-Lan Kwak 
 BIOLOGICAL & PHARMACEUTICAL BULLETIN, Vol.36(7) : 1126-1133, 2013 
Journal Title
Issue Date
erythropoietin ; hypoxia ; Ser-105 ; GATA-4 ; phosphorylation ; ubiquitination
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.
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Anesthesiology and Pain Medicine (마취통증의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kwak, Young Lan(곽영란) ORCID logo https://orcid.org/0000-0002-2984-9927
Kim, Ji Ho(김지호)
Shin, Eun Jung(신은정)
Shim, Jae Kwang(심재광) ORCID logo https://orcid.org/0000-0001-9093-9692
Jun, Ji Hae(전지혜) ORCID logo https://orcid.org/0000-0002-8080-0715
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