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.

Neonatal exposure to oestradiol increases dopaminergic transmission in nucleus accumbens and morphine‐induced conditioned place preference in adult female rats

“… In this regard, the nerve growth factor IB or Nur77 is a transcriptional factor in dopaminergic neurones that promotes survival and cell death depending on its subcellular localisation . In this sense, E 2 reduces the cytoplasmic accumulation of Nur77, which promotes cellular survival …”

“…50 In this sense, E 2 reduces the cytoplasmic accumulation of Nur77, which promotes cellular survival. 51 Sex hormones can influence different brain functions such as cognition, motor regulation and rewarding behaviour, and modulate the release and content of neurotransmitters. 24,52 We have recently shown that the neonatal administration of EV and testosterone propionate (TP) in male rats produces an increase in the content and release of DA in SN-VTA and NAcc, respectively.…”

Characteristics of Nur77 and its ligands as potential anticancer compounds (Review)

“…For example, following glutamate treatment, Nur77 is translocated from the nucleus to the cytosol and mitochondria in rat cerebellar granule neurons ( 42 ). Additionally, by inhibiting the migration of Nur77 from the nucleus to the cytoplasm, 17β-estradiol can delay 6-hydroxydopamine-induced apoptosis ( 43 ). Endogenous insulin-like growth factor-binding protein 3 has been reported to facilitate the phosphorylation of Nur77 and the export of Nur77 from the nucleus to the cytoplasm, which is vital in intrinsic apoptosis ( 44 ).…”

Biochemical effects of estrogens in non-reproductive organs

“…Estrogens prevent in vitro the toxical effect of 6-hydroxydophamine on PC12 cells [37]. It is shown that its effect results in translocation of the nuclear transcription factor Nur77 to cytoplasm with following apoptosis, and E2 inhibits translocation and prevents apoptosis of PC12 cells.…”