Role of the HIF-1/Nur77 axis in the regulation of the tyrosine hydroxylase expression by insulin in PC12 cells

被引:13
作者
Fiory, Francesca [1 ,2 ]
Mirra, Paola [1 ,2 ]
Nigro, Cecilia [1 ,2 ]
Pignalosa, Francesca Chiara [1 ,2 ]
Zatterale, Federica [1 ,2 ]
Ulianich, Luca [1 ,2 ]
Prevete, Nella [1 ,2 ]
Formisano, Pietro [1 ,2 ]
Beguinot, Francesco [1 ,2 ]
Miele, Claudia [1 ,2 ]
机构
[1] Federico II Univ Naples, Dept Translat Med, Via Pansini 5, I-80131 Naples, Italy
[2] CNR, Natl Council Res, Dept Translat Med, Inst Expt Endocrinol & Oncol,URT Genom Diabet, Via Pansini 5, I-80131 Naples, Italy
关键词
dopamine (DA); hypoxia inducible factor 1-alpha (HIF-1); insulin; Nur77; tyrosine hydroxylase (TH); HYPOXIA RESPONSE ELEMENTS; INDUCIBLE FACTOR-I; GENE-EXPRESSION; TRANSCRIPTION FACTOR; PARKINSONS-DISEASE; BIOCHEMICAL PATHWAYS; OXIDATIVE STRESS; RESISTANCE; INDUCTION; GLUCOSE;
D O I
10.1002/jcp.27898
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Tyrosine hydroxylase (TH), catalyzing the conversion of tyrosine into l-DOPA, is the rate-limiting enzyme in dopamine synthesis. Defects in insulin action contribute to alterations of TH expression and/or activity in the brain and insulin increases TH levels in 1-methyl-4-phenylpyridinium (MPP+)-treated neuronal cells. However, the molecular mechanisms underlying the regulation of TH by insulin have not been elucidated yet. Using PC12 cells, we show for the first time that insulin increases TH expression in a biphasic manner, with a transient peak at 2hr and a delayed response at 16hr, which persists for up to 24hr. The use of a dominant negative hypoxia-inducible factor 1-alpha (HIF-1) and its pharmacological inhibitor chetomin, together with chromatin immunoprecipitation (ChIP) experiments for the specific binding to TH promoter, demonstrate the direct role of HIF-1 in the early phase. Moreover, ChIP experiments and transfection of a dominant negative of the nerve growth factor IB (Nur77) indicate the involvement of Nur77 in the late phase insulin response, which is mediated by HIF-1. In conclusion, the present study shows that insulin regulates TH expression through HIF-1 and Nur77 in PC12 cells, supporting the critical role of insulin signaling in maintaining an appropriate dopaminergic tone by regulating TH expression in the central nervous system.
引用
收藏
页码:11861 / 11870
页数:10
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