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J Biol Chem, Vol. 274, Issue 9, 5909-5918, February 26, 1999

Molecular Mechanisms of Thyroid Hormone-stimulated Steroidogenesis in Mouse Leydig Tumor Cells
INVOLVEMENT OF THE STEROIDOGENIC ACUTE REGULATORY (StAR) PROTEIN

From the Department of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland

Using a mouse Leydig tumor cell line, we explored the mechanisms involved in thyroid hormone-induced steroidogenic acute regulatory (StAR) protein gene expression, and steroidogenesis. Triiodothyronine (T₃) induced a ~3.6-fold increase in the steady-state level of StAR mRNA which paralleled with those of the acute steroid response (~4.0-fold), as monitored by quantitative reverse transcriptase-polymerase chain reaction assay and progesterone production, respectively. The T₃-stimulated progesterone production was effectively inhibited by actinomycin-D or cycloheximide, indicating the requirement of on-going mRNA and protein synthesis. T₃ displayed the highest affinity of [¹²⁵I]iodo-T₃ binding and was most potent in stimulating StAR mRNA expression. In accordance, T₃ significantly increased testosterone production in primary cultures of adult mouse Leydig cells. The T₃ and human chorionic gonadotropin (hCG) effects on StAR expression were similar in magnitude and additive. Cells expressing steroidogenic factor 1 (SF-1) showed marginal elevation of StAR expression, but coordinately increased T₃-induced StAR mRNA expression and progesterone levels. In contrast, overexpression of DAX-1 markedly diminished the SF-1 mRNA expression, and concomitantly abolished T₃-mediated responses. Noteworthy, T₃ augmented the SF-1 mRNA expression while inhibition of the latter by DAX-1 strongly impaired T₃ action. Northern hybridization analysis revealed four StAR transcripts which increased 3-6-fold following T₃ stimulation. These observations clearly identified a regulatory cascade of thyroid hormone-stimulated StAR expression and steroidogenesis that provides novel insight into the importance of a thyroid-gonadal connection in the hormonal control of Leydig cell steroidogenesis.

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