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Role of the HIF‐1α/Nur77 axis in the regulation of the tyrosine hydroxylase expression by insulin in PC12 cells
Author(s) -
Fiory Francesca,
Mirra Paola,
Nigro Cecilia,
Pignalosa Francesca Chiara,
Zatterale Federica,
Ulianich Luca,
Prevete Nella,
Formisano Pietro,
Beguinot Francesco,
Miele Claudia
Publication year - 2019
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.27898
Subject(s) - tyrosine hydroxylase , insulin , nerve growth factor ib , endocrinology , medicine , insulin receptor , chromatin immunoprecipitation , biology , tyrosine , microbiology and biotechnology , dopaminergic , dopamine , transcription factor , gene expression , nuclear receptor , gene , biochemistry , insulin resistance , promoter
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 2 hr and a delayed response at 16 hr, which persists for up to 24 hr. The use of a dominant negative hypoxia‐inducible factor 1‐alpha (HIF‐1α) and its pharmacological inhibitor chetomin, together with chromatin immunoprecipitation (ChIP) experiments for the specific binding to TH promoter, demonstrate the direct role of HIF‐1α 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‐1α. In conclusion, the present study shows that insulin regulates TH expression through HIF‐1α 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.