흰쥐 해마 신경 세포에서 erythropoietin과 carbamylated erythropoietin의 histone deacetylase 5 인산화 및 핵외수송 촉진 효과에 대한 연구

Abstract

Erythropoietin (EPO) 는 신경퇴화 동물모델에서 신경영양적 효과를 생성한다. 그러나, EPO 의 임상적 사용은 혈전성 위험에 의해 제한된다. 혈전성 위험이 없는 carbamylated erythropoietin (CEPO) 의 분자 메커니즘은 아직 불완전하지만 새로운 신경보호적, 신경영양적 약물로 제안된다. 이 연구는 EPO 와 CEPO 의 작용에 histone deacetylase 5 (HDAC5) 의 새로운 역할을 제시한다. EPO 와 CEPO 는 protein kinase D (PKD) 의존적 경로를 통해, HDAC5 의 특정 위치인 Ser259 와 Ser498 의 인산화를 조절한다. EPO 와 CEPO 는 HDAC5-GFP 를 발현한 흰쥐의 해마신경세포에서 HDAC5 의 핵외수송을 빠르게 촉진시킨다. 결과적으로, EPO 와 CEPO 는 myocyte enhancer factor-2 (MEF2) 의 표적 유전자의 발현을 증가시킨다. 이러한 결과들은 EPO 와 CEPO 가 HDAC5 의 인산화 조절을 통해 MEF2 표적 유전자의 발현을 조절하는 것을 밝히며, HDAC5 가 EPO 와 CEPO 의 치료 작용에 기여하는 잠재적인 메커니즘이 될 수 있음을 제안한다.|Erythropoietin (EPO) produces neurotrophic effects in animal model of neurodegeneration. However, clinical use of EPO is limited due to thrombotic risk. Carbamylated EPO (CEPO), devoid of thrombotic risk, has been proposed as a novel neuroprotective and neurotrophic agent although the molecular mechanisms of CEPO remain incomplete. Here, this study shows a novel role of histone deacetylase 5 (HDAC5) in the actions of EPO and CEPO. EPO and CEPO regulate the HDAC5 phosphorylation at two critical sites, Ser259 and Ser498 through a protein kinase D (PKD)-dependent pathway. In addition, EPO and CEPO rapidly stimulate nuclear export of HDAC5 in rat hippocampal neurons which express HDAC5-GFP. Consequently, EPO and CEPO enhance the myocyte enhancer factor-2 (MEF2) target gene expression. Taken together, these results reveal that EPO and CEPO mediate MEF2 target gene expression via the regulation of HDAC5 phosphorylation at Ser259 and Ser498, and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of EPO and CEPO.; Erythropoietin (EPO) produces neurotrophic effects in animal model of neurodegeneration. However, clinical use of EPO is limited due to thrombotic risk. Carbamylated EPO (CEPO), devoid of thrombotic risk, has been proposed as a novel neuroprotective and neurotrophic agent although the molecular mechanisms of CEPO remain incomplete. Here, this study shows a novel role of histone deacetylase 5 (HDAC5) in the actions of EPO and CEPO. EPO and CEPO regulate the HDAC5 phosphorylation at two critical sites, Ser259 and Ser498 through a protein kinase D (PKD)-dependent pathway. In addition, EPO and CEPO rapidly stimulate nuclear export of HDAC5 in rat hippocampal neurons which express HDAC5-GFP. Consequently, EPO and CEPO enhance the myocyte enhancer factor-2 (MEF2) target gene expression. Taken together, these results reveal that EPO and CEPO mediate MEF2 target gene expression via the regulation of HDAC5 phosphorylation at Ser259 and Ser498, and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of EPO and CEPO.