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Erythropoietin-activated ERK/MAP kinase enhances GATA-4 acetylation via phosphorylation of serine 261 of GATA-4

Authors

  • Ji Hae Jun,

    1. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
    2. Anaesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
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  • Jae-Kwang Shim,

    1. Anaesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
    2. Department of Anaesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
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  • Hyun-Mo Ryoo,

    Corresponding author
    1. Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, Republic of Korea
    • Department of Molecular Genetics, School of Dentistry, Seoul National University, 28 Yeongun-dong, Jongno-gu, Seoul 110-749, Republic of Korea.
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  • Young-Lan Kwak

    Corresponding author
    1. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
    2. Anaesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
    3. Department of Anaesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
    • Department of Anaesthesiology and Pain Medicine, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemum-gu, Seoul 120-752, Republic of Korea.
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  • Conflicts of interest: nothing to declare.

Abstract

GATA-4, a zinc finger transcription factor, plays a critical role in heart development. Previous studies have shown that p300-targeted GATA-4 acetylation increases GATA-4 stability and transcriptional activity, which then stimulates hypertrophy of cardiomyocyte. Erythropoietin (EPO), an essential hypoxia-induced hormone for normal erythropoiesis, is known to exert cardioprotective effects against heart disease of either ischemic or non-ischemic origins. Although, various action mechanisms of EPO have been proposed in the diseased heart, its action mechanism in normal condition has not been investigated. In this study, we aimed to investigate the influence of EPO-induced ERK signaling on the regulation of GATA-4 protein action. EPO treatment increased the protein level of endogenous GATA-4 via ERK signaling pathway. Inhibition of ERK activity by U0126, suppressed EPO-induced expression of GATA-4 protein in rat cardiac myocytes. In addition, ERK activation by over-expression of constitutively active MEK1 strongly increased GATA-4 phosphorylation and subsequently enhanced its acetylation in P19 cells. EPO-induced ERK activation further increased the association of GATA-4 with p300. On the other hand, knock-down of p300 using siRNA diminished ERK-induced GATA-4 acetylation. As EPO-induced GATA-4 phosphorylation via ERK signaling pathway directly correlated with GATA-4 acetylation, we investigated to identify the ERK-dependent phosphorylation sites in GATA-4. Site-directed mutagenesis implicated that Ser-261 in GATA-4 played an important role for ERK-mediated GATA-4 acetylation. Taken together, these results indicated that EPO-induced ERK signaling activation increased GATA-4 phosphorylation and acetylation, partly via increase in the association between GATA-4 and p300, and these processes required the phosphorylation of GATA-4 at Ser-261 residue. J. Cell. Physiol. 228: 190–197, 2013. © 2012 Wiley Periodicals, Inc.

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