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Triiodothyronine Decreases the Activity of the Proximal Promoter (PII) of the Aromatase Gene in the Mouse Sertoli Cell Line, TM4

Departments of Pharmaco-Biology (V.P., A.C., C.G.) and Cell Biology (A.C., S.A.), Centro Sanitario Faculty of Pharmacy (S.C.), University of Calabria 87030 Arcavacata di Rende (CS), Italy; and Department of Internal Medicine (M.Y., M.J.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75235-8857

Address all correspondence and requests for reprints to: Professor Sebastiano Andò, Department of Cell Biology, University of Calabria, Arcavacata di Rende (CS) 87030, Italy. E-mail: sebastiano.ando{at}unical.it)

Estrogens and thyroid hormones play a significant role in regulating functions and development of the testis. The synthesis of estrogens from androgens is catalyzed by the enzyme complex termed aromatase, which in the testis displays an age-related cellular compartmentalization, primarily in Sertoli cells in immature animals, whereas in adults it is expressed in Leydig and germ cells. T₃ induces a precocious terminal differentiation of prepubertal Sertoli cells together with a dramatic decrease of their aromatase activity. In the present work, we have examined the mechanism by which T₃ exerts this inhibitory action on aromatase expression.

As an experimental model, we used the mouse Sertoli cell line TM4, which conserves a large spectrum of functional features present in immature Sertoli cells. For instance, after revealing the presence of aromatase by immunocytochemistry and measuring its enzymatic activity, we confirmed in this cell line the functional events previously characterized in primary cultures of immature rat Sertoli cells: 1) a strong stimulation of aromatase activity by dibutyryl-cAMP [(Bu)₂cAMP] (simulating FSH action); and 2) the inhibition of aromatase activity by incubation with T₃ under basal condition and after (Bu)₂cAMP stimulation.

After identifying promoter II as the regulatory region located immediately upstream of the transcriptional initiation site in the TM4 cell line by rapid amplification of cDNA ends analysis, we conducted experiments to examine the molecular mechanism by which thyroid hormones modulate aromatase gene expression in this cell line. TM4 cells were transfected with plasmids containing different segments of the rat promoter II sequence ligated to a luciferase reporter gene. Analysis of the activities of these promoter fusions demonstrated that T₃ inhibits basal and (Bu)₂cAMP-stimulated activity of the aromatase promoter. This effect was not revealed in T₃-treated cells transfected with construct in which the steroidogenic factor-1 (SF-1) response element was mutated. These results indicate that the inhibitory effect of T₃ requires the integrity of the SF-1 response element and are further supported in the EMSA. The EMSA experiments demonstrated that thyroid hormone/thyroid receptor 1 complex (TH/TR1) is able to compete with SF-1 in binding to oligonucleotides containing an SF-1 motif, an element essential for the activity of the PII aromatase promoter. The findings suggest that the binding of the thyroid hormone/thyroid receptor 1 complex to the SF-1 motif is the molecular mechanism by which T₃ exerts an inhibitory effect on aromatase gene expression in the TM4 cell line.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ  |  SF-1

Ligands:   Thyroid hormone

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