Role of the HIF-1α/Nur77 axis in the regulation of the tyrosine hydroxylase expression by insulin in PC12 cells.
Animals
Cell Hypoxia
/ physiology
Dopamine
/ metabolism
Hypoxia-Inducible Factor 1, alpha Subunit
/ metabolism
Insulin
/ metabolism
Neurons
/ drug effects
Nuclear Receptor Subfamily 4, Group A, Member 1
/ metabolism
PC12 Cells
Rats
Transcriptional Activation
/ physiology
Tyrosine 3-Monooxygenase
/ drug effects
Up-Regulation
Nur77
dopamine (DA)
hypoxia inducible factor 1-alpha (HIF-1α)
insulin
tyrosine hydroxylase (TH)
Journal
Journal of cellular physiology
ISSN: 1097-4652
Titre abrégé: J Cell Physiol
Pays: United States
ID NLM: 0050222
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
17
04
2018
accepted:
09
11
2018
pubmed:
12
12
2018
medline:
12
5
2020
entrez:
12
12
2018
Statut:
ppublish
Résumé
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.
Substances chimiques
Hif1a protein, rat
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
Insulin
0
Nr4a1 protein, rat
0
Nuclear Receptor Subfamily 4, Group A, Member 1
0
Tyrosine 3-Monooxygenase
EC 1.14.16.2
Dopamine
VTD58H1Z2X
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
11861-11870Informations de copyright
© 2018 Wiley Periodicals, Inc.