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Graduate School of Allied Health Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyouku, Tokyo, Japan
¹ Department of Endocrinology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyouku, Tokyo, Japan
² Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyouku, Tokyo, Japan
³ Laboratory of Functional Genomics, Department of Medical Genome Science, Graduate School of Frontier Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo, Japan
⁴ Division for Sex Differentiation, National Institute for Basic Biology, National Institutes of Natural Sciences, Higashiyama 5-1, Myondaiji-cho, Okazaki, Japan

(Requests for offprints should be addressed to R Asakai; Email: asakai{at}jiu.ac.jp)

(R Asakai, Y Aoyama and Y Kamei are now at Josai International University, Faculty of Pharmaceutical Sciences, Department of Morphophysiology, 1 Gumyo Togane, Chiba 283-8555, Japan)

Several steroidogenic cell lines of granulosa cells (GC) have been used to elucidate differentiation mechanisms of GC during folliculogenesis. These cell lines, however, are of limited usefulness since they have lost some of their differentiation potential. The transcription factor adrenal-4 binding protein (Ad4BP), also known as steroidogenic factor-1 or NR5A1, is essential for the expression of all P-450 steroidogenic enzymes. By transfection with the Ad4BP gene together with SV40 DNA, we have generated several steroidogenic cell lines. One selective clone, named 4B2, retained its steroidogenic potential and was therefore analyzed in depth. This cell line responded to 8-Br-cAMP by displaying differentiation characteristics similar to those occurring in the differentiation process of primary cultured GC, including enhanced progesterone secretion, a cell shape change from a fibroblastic to epithelioid conformation, elongated mitochondria, increased gap junction formation and inhibition of cell proliferation. Prostaglandin E₂ (PGE₂), an intraovarian regulator of GC, stimulated cAMP production, and this eicosanoid, like 8-Br-cAMP, induced differentiation properties with the exception of cell conformation in 4B2 cells. These results suggest that expression of Ad4BP may provide the basis for a repertoire of cAMP-sensitive differentiation properties, including morphological alterations and growth inhibition. Thus, the 4B2 cell line may serve as a tool for elucidation of differentiation mechanisms that are under the control of Ad4BP.