title: 17β-estradiol delays 6-OHDA-induced apoptosis by acting on Nur77 translocation from the nucleus to the cytoplasm.
abstract: Nuclear receptors (Nurs) represent a large family of gene expression regulating proteins. Gathering evidence indicates an important role for Nurs as transcription factors in dopamine neurotransmission. Nur77, a member of the Nur superfamily, plays a role in mediating the effects of antiparkinsonian and neuroleptic drugs. Besides, Nur77 survival and apoptotic roles depend largely on its subcellular localization. Estrogens are known for their neuroprotective properties, as demonstrated in animal and clinical studies. However, their action on Nur77 translocation pertaining to neuroprotection has not been investigated yet. The aim of our study was to perform a kinetic study on the effect of neurotoxic 6-hydroxydopamine (6-OHDA) and 17β-estradiol (E2) on the subcellular localization of Nur77 with reference to the modulation of apoptosis in PC12 cells. Our results demonstrate that E2 administration alone does not affect Nur77 cytoplasmic/nuclear ratio, mRNA levels, or apoptosis in PC12 cells. The neurotoxin 6-OHDA significantly enhances cytoplasmic localization of Nur77 after merely 3 h, while precipitating apoptosis. 6-OHDA also increases Nur77 transcription, which could partly explain the rise in cytoplasmic localization of the protein. Finally, treatment with both E2 and 6-OHDA delays Nur77 accumulation in the cytoplasm and delays cell death for a few hours in our cellular paradigm. Pre-treatment with E2 does not alter the increase in levels of Nur77 mRNA produced by 6-OHDA, suggesting that a raise in nuclear translocation is likely responsible for the stabilization of the cytoplasmic/nuclear ratio until 6 h. These results suggest an intriguing cooperation between E2 and Nur77 toward cellular fate guidance.
authors.affiliation: Department of Medical Biology and Research Group in Neuroscience, Université du Québec à Trois-Rivières, C.P. 500, Trois-Rivières, QC, G9A 5H7, Canada.
authors.forename: Justine
authors.initials: J
authors.lastname: Renaud
authors.forename: Keith
authors.initials: K
authors.lastname: Chiasson
authors.forename: Julie
authors.initials: J
authors.lastname: Bournival
authors.forename: Claude
authors.initials: C
authors.lastname: Rouillard
authors.forename: Maria-Grazia
authors.initials: MG
authors.lastname: Martinoli
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D016716:PC12 Cells; D051381:Rats
chemical_list: D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D004958:Estradiol; D016627:Oxidopamine