Estrogen Receptor-β Mediates Dihydrotestosterone-Induced Stimulation of the Arginine Vasopressin Promoter in Neuronal Cells

Arginine vasopressin (AVP) is a neuropeptide involved in the regulation of fluid balance, stress, circadian rhythms, and social behaviors. In the brain, AVP is tightly regulated by gonadal steroid hormones in discrete regions with gonadectomy abolishing and testosterone replacement restoring normal AVP expression in adult males. Previous studies demonstrated that 17β-estradiol, a primary metabolite of testosterone, is responsible for restoring most of the AVP expression in the brain after castration. However, 5α-dihydrotestosterone (DHT) has also been shown to play a role in the regulation of AVP expression, thus implicating the involvement of both androgen and estrogen receptors (ER). Furthermore, DHT, through its conversion to 5α-androstane-3β,17β-diol, has been shown to modulate estrogen response element-mediated promoter activity through an ER pathway. The present study addressed two central hypotheses: 1) that androgens directly modulate AVP promoter activity and 2) the effect is mediated by an estrogen or androgen receptor pathway. To that end, we overexpressed androgen receptor, ERβ, and ERβ splice variants in a neuronal cell line and measured AVP promoter activity using a firefly luciferase reporter assay. Our results demonstrate that DHT and its metabolite 5α-androstane-3β,17β-diol stimulate AVP promoter activity through ERβ in a neuronal cell line.

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Effects of interleukin-1 and interleukin-6 on the expression of metallothionein in a human neuronal cell line: evidence for an acute-phase response in the brain

Neurochemistry International ◽

10.1016/0197-0186(92)92088-l ◽

1992 ◽

Vol 21 ◽

pp. C15

Author(s):

J. Bauer ◽

U. Ganter ◽

P. Weiss ◽

U. Jonas ◽

M. Berger

Keyword(s):

Cell Line ◽

Acute Phase ◽

Interleukin 6 ◽

Acute Phase Response ◽

Interleukin 1 ◽

Neuronal Cell ◽

Phase Response ◽

Neuronal Cell Line ◽

Human Neuronal Cell ◽

The Brain

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Rhes, a striatal-enriched protein, promotes mitophagy via Nix

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1912868116 ◽

2019 ◽

Vol 116 (47) ◽

pp. 23760-23771 ◽

Cited By ~ 9

Author(s):

Manish Sharma ◽

Uri Nimrod Ramírez-Jarquín ◽

Oscar Rivera ◽

Melissa Kazantzis ◽

Mehdi Eshraghi ◽

...

Keyword(s):

Cell Death ◽

Cell Line ◽

Neuronal Cell ◽

Dependent Manner ◽

Systemic Injection ◽

Neuronal Cell Line ◽

In The Wild ◽

Striatal Lesion ◽

The Brain

Elimination of dysfunctional mitochondria via mitophagy is essential for cell survival and neuronal functions. But, how impaired mitophagy participates in tissue-specific vulnerability in the brain remains unclear. Here, we find that striatal-enriched protein, Rhes, is a critical regulator of mitophagy and striatal vulnerability in brain. In vivo interactome and density fractionation reveal that Rhes coimmunoprecipitates and cosediments with mitochondrial and lysosomal proteins. Live-cell imaging of cultured striatal neuronal cell line shows Rhes surrounds globular mitochondria, recruits lysosomes, and ultimately degrades mitochondria. In the presence of 3-nitropropionic acid (3-NP), an inhibitor of succinate dehydrogenase, Rhes disrupts mitochondrial membrane potential (ΔΨm) and promotes excessive mitophagy and cell death. Ultrastructural analysis reveals that systemic injection of 3-NP in mice promotes globular mitochondria, accumulation of mitophagosomes, and striatal lesion only in the wild-type (WT), but not in the Rhes knockout (KO), striatum, suggesting that Rhes is critical for mitophagy and neuronal death in vivo. Mechanistically, Rhes requires Nix (BNIP3L), a known receptor of mitophagy, to disrupt ΔΨm and promote mitophagy and cell death. Rhes interacts with Nix via SUMO E3-ligase domain, and Nix depletion totally abrogates Rhes-mediated mitophagy and cell death in the cultured striatal neuronal cell line. Finally, we find that Rhes, which travels from cell to cell via tunneling nanotube (TNT)-like cellular protrusions, interacts with dysfunctional mitochondria in the neighboring cell in a Nix-dependent manner. Collectively, Rhes is a major regulator of mitophagy via Nix, which may determine striatal vulnerability in the brain.

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Effects of the G(−656)A variant on CREB1 promoter activity in a neuronal cell line: Interactions with gonadal steroids and stress

Molecular Psychiatry ◽

10.1038/mp.2008.23 ◽

2008 ◽

Vol 14 (4) ◽

pp. 390-397 ◽

Cited By ~ 6

Author(s):

G S Zubenko ◽

H B Hughes

Keyword(s):

Cell Line ◽

Promoter Activity ◽

Neuronal Cell ◽

Gonadal Steroids ◽

Neuronal Cell Line

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The Androgen Metabolite, 5α-Androstane-3β, 17β-Diol, Is a Potent Modulator of Estrogen Receptor-β1-Mediated Gene Transcription in Neuronal Cells

Endocrinology ◽

10.1210/en.2004-0871 ◽

2005 ◽

Vol 146 (1) ◽

pp. 147-155 ◽

Cited By ~ 100

Author(s):

Toni R. Pak ◽

Wilson C. J. Chung ◽

Trent D. Lund ◽

Laura R. Hinds ◽

Colin M. Clay ◽

...

Keyword(s):

Estrogen Receptor ◽

Gene Transcription ◽

Promoter Activity ◽

Molecular Mechanisms ◽

Prostate Gland ◽

Neuronal Cells ◽

Neuronal Cell ◽

Luciferase Reporter ◽

17Β Estradiol ◽

The Brain

5α-Androstane-3β, 17β-diol (3βAdiol) is a metabolite of the potent androgen, 5α-dihydrotestosterone. Recent studies showed that 3βAdiol binds to estrogen receptor (ER)-β and regulates growth of the prostate gland through an estrogen, and not androgen, receptor-mediated pathway. These data raise the possibility that 3βAdiol could regulate important physiological processes in other tissues that produce 3βAdiol, such as the brain. Although it is widely accepted that the brain is a target for 5α-dihydrotestosterone action, there is no evidence that 3βAdiol has a direct action in neurons. To explore the molecular mechanisms by which 3βAdiol might act to modulate gene transcription in neuronal cells, we examined whether 3βAdiol activates ER-mediated promoter activity and whether ER transactivation is facilitated by a classical estrogen response element (ERE) or an AP-1 complex. The HT-22 neuronal cell line was cotransfected with an expression vector containing ERα, ER-β1, or the ERβ splice variant, ER-β2 and one of two luciferase-reporter constructs containing either a consensus ERE or an AP-1 enhancer site. Cells were treated with 100 nm 17β-estradiol, 100 nm 3βAdiol, or vehicle for 15 h. We show that 3βAdiol activated ER-β1-induced transcription mediated by an ERE equivalent to that of 17β-estradiol. By contrast, 3βAdiol had no effect on ERα- or ER-β2-mediated promoter activity. Moreover, ER-β1 stimulated transcription mediated by an ERE and inhibited transcription by an AP-1 site in the absence of ligand binding. These data provide evidence for activation of ER signaling pathways by an androgen metabolite in neuronal cells.

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