Testosterone/bicalutamide antagonism at the predicted extracellular androgen binding site of ZIP9

Bulldan, Ahmed; Malviya, Viveka Nand; Upmanyu, Neha; Konrad, Lutz; Scheiner‐Bobis, Georgios

doi:10.1016/j.bbamcr.2017.09.012

Cited by 19 publications

(28 citation statements)

References 64 publications

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“…HF is an active metabolite of pure AR antagonist, flutamide, which does not block membraneinitiated androgen actions [12,[37][38][39]. In contrast, Bic was demonstrated to inhibit activation of both AR and ZIP9 [40,41].…”

Section: Resultsmentioning

confidence: 99%

Crosstalk between Androgen-ZIP9 Signaling and Notch Pathway in Rodent Sertoli Cells

Kamińska

Marek

Pardyak

et al. 2020

IJMS

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Our recent study demonstrated altered expression of Notch ligands, receptors, and effector genes in testes of pubertal rats following reduced androgen production or signaling. Herein we aimed to explore the role of nuclear androgen receptor (AR) and membrane androgen receptor (Zrt- and Irt-like protein 9; ZIP9) in the regulation of Notch pathway activation in rodent Sertoli cells. Experiments were performed using TM4 and 15P-1 Sertoli cell lines and rat primary Sertoli cells (PSC). We found that testosterone (10−8 M–10−6 M) increased the expression of Notch1 receptor, its active form Notch1 intracellular domain (N1ICD) (p < 0.05, p < 0.01, p < 0.001), and the effector genes Hey1 (p < 0.05, p < 0.01, p < 0.001) and Hes1 (p < 0.05, p < 0.001) in Sertoli cells. Knockdown of AR or ZIP9 as well as antiandrogen exposure experiments revealed that (i) action of androgens via both AR and ZIP9 controls Notch1/N1ICD expression and transcriptional activity of recombination signal binding protein (RBP-J), (ii) AR-dependent signaling regulates Hey1 expression, (iii) ZIP9-dependent pathway regulates Hes1 expression. Our findings indicate a crosstalk between androgen and Notch signaling in Sertoli cells and point to cooperation of classical and non-classical androgen signaling pathways in controlling Sertoli cell function.

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Section: Resultsmentioning

confidence: 99%

Crosstalk between Androgen-ZIP9 Signaling and Notch Pathway in Rodent Sertoli Cells

Kamińska

Marek

Pardyak

et al. 2020

IJMS

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“…On the other hand, as evidenced by studies on Sertoli cell‐specific AR knockout (SCARKO) mice the expression of claudin‐11, another TJ protein important for BTB integrity, is regulated by testosterone action through the AR (Tan et al ., ; Willems et al ., ). In agreement with previous in vitro findings from rat and mouse Sertoli cells (Kaitu'u‐Lino et al ., ; Bulldan et al ., ), in TM4 cells we observed upregulation of both claudin‐11 and claudin‐5 mRNA and protein following testosterone treatment.…”

Section: Discussionmentioning

confidence: 97%

“…Finally, to explore the interplay between androgen-regulated cellular functions and Notch signaling, we investigated the expression of claudin-5 and claudin-11 after DAPT treatment and RBP-J silencing. Recently, Bulldan et al (2017) demonstrated that blockade of ZIP9 receptor in AR-deficient rat Sertoli cells resulted in decreased claudin-5 and ZO-1 and disturbed tight junction (TJ) formation between the cells, indicating a role of ZIP9 in BTB function. On the other hand, as evidenced by studies on Sertoli cell-specific AR knockout (SCARKO) mice the expression of claudin-11, another TJ protein important for BTB integrity, is regulated by testosterone action through the AR (Tan et al, 2005;Willems et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Notch signaling regulates nuclear androgen receptor AR and membrane androgen receptor ZIP9 in mouse Sertoli cells

et al. 2019

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Background Notch signaling pathway is involved in contact‐dependent communication between the cells of seminiferous epithelium, and its proper activity is important for undisturbed spermatogenesis. Objectives The aim was to assess the effect of Notch pathway inhibition on the expression of nuclear (AR) and membrane (ZIP9) androgen receptors and androgen‐regulated genes, claudin‐5 and claudin‐11, in TM4 mouse Sertoli cell line. Materials and methods DAPT (γ‐secretase inhibitor) treatment and recombination signal binding protein silencing were employed to reduce Notch signaling, whereas immobilized ligands were used to activate Notch pathway in TM4 cells. To reveal specific effect of each androgen receptor, AR or ZIP9 silencing was performed. Results Notch pathway inhibition increased the expression of AR and ZIP9 mRNA and proteins (p < 0.01; p < 0.05) in TM4 cells, whereas incubation with Notch ligands, rDLL1 or rJAG1, reduced AR (p < 0.01; p < 0.001) and ZIP9 (p < 0.05; p < 0.01) expressions, respectively. Testosterone enhanced the expression of both receptors (p < 0.05; p < 0.01). Androgen‐regulated claudin‐5 and claudin‐11 (p < 0.01; p < 0.001) and cAMP (p < 0.001) were elevated in Notch‐inhibited cells, while activation of Notch signaling by DLL1 or JAG1 reduced claudin‐11 or claudin‐5 level (p < 0.01; p < 0.001), respectively. Discussion Our findings indicate opposite effect of Notch and androgen signaling on the expression of androgen receptors in TM4 cells. We demonstrated that AR expression is regulated by DLL1‐mediated Notch signaling, whereas JAG1 is involved in the regulation of ZIP9. The expression of both claudins and cAMP production is under inhibitory influence of Notch pathway. The effects of Notch signaling on claudin‐5 and claudin‐11 expression are mediated by ZIP9 and AR, respectively. Conclusion Notch signaling may be considered as an important pathway controlling Sertoli cell physiology, and its alterations may contribute to disturbed response of Sertoli cells to androgens.

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“…The fact that HT develops following castration of the androgen receptor-deficient Tfm rats provides strong evidence that the anti-hypertensive effects of TES on the vasculature and kidney rely upon nongenomic mechanism(s) independent of the classic cytosolic AR that mediates the genomic effects of this hormone. In reproductive tissue cultures, AR-independent actions of TES are mediated by membrane receptors that can bind TES, such as the ZIP9 Zinc transporter [59] or other membrane-associated androgen receptor proteins [60]. These receptors appear to mediate the effects of TES via rapid activation of ERK1/2, Akt, and CREB signaling cascades.…”

Section: Mechanisms Underlying Anti-hypertensive Effects Of Androgensmentioning

confidence: 99%

Hypogonadal hypertension in male Sprague-Dawley rats is renin-angiotensin system-dependent: role of endogenous androgens

2020

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Background: Acutely, testosterone (TES) and other androgens are efficacious vasodilators, both in vitro and in vivo; however, their long-term effects on arterial blood pressure (BP) remain unclear. It was hypothesized that endogenous androgens exert long-term anti-hypertensive effects on systemic BP through a combination of genomic and nongenomic effects to enhance vasodilation of the systemic vasculature. Methods: The long-term effects of endogenous TES and exogenous TES replacement therapy (TRT) on BP were studied in intact (InT) and castrated (CsX) male Sprague-Dawley (SD) and testicular-feminized male (Tfm, androgen receptor defective) rats (12 weeks old). Systolic BP (tail-cuff plethysmography) was determined weekly for 15 weeks in InT-control and CsX rats. Some CsX-SD rats received androgen replacement therapy at 10-15 weeks with TES-enanthate (TRT; 1.75 mg/kg, 2x/week) or DHT-enanthate (DRT; 1.00 mg/kg. 2x/week) and a separate group of CsX-SD rats received losartanpotassium in drinking water (LST, 250 mg/L) for the entire 15 week period. Expression of renin, angiotensinogen (Agt), angiotensin converting enzyme (ACE), and angiotensin II type I receptor (AT 1 R) mRNA in kidney and aorta were determined by real-time PCR (rt-PCR) and plasma renin levels were determined by radioimmunoassay.

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Testosterone/bicalutamide antagonism at the predicted extracellular androgen binding site of ZIP9

Cited by 19 publications

References 64 publications

Crosstalk between Androgen-ZIP9 Signaling and Notch Pathway in Rodent Sertoli Cells

Crosstalk between Androgen-ZIP9 Signaling and Notch Pathway in Rodent Sertoli Cells

Notch signaling regulates nuclear androgen receptor AR and membrane androgen receptor ZIP9 in mouse Sertoli cells

Hypogonadal hypertension in male Sprague-Dawley rats is renin-angiotensin system-dependent: role of endogenous androgens

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