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      PPAR-gamma coactivator-1alpha regulates progesterone production in ovarian granulosa cells with SF-1 and LRH-1.

      Molecular Endocrinology

      Adenoviridae, genetics, Animals, COS Cells, Cell Differentiation, physiology, Cell Line, Cells, Cultured, Cercopithecus aethiops, Chromatin Immunoprecipitation, DAX-1 Orphan Nuclear Receptor, metabolism, Female, Genetic Vectors, Granulosa Cells, cytology, Heat-Shock Proteins, Humans, Immunohistochemistry, Immunoprecipitation, Mesenchymal Stromal Cells, Mice, Mice, Inbred C57BL, Progesterone, biosynthesis, Rats, Rats, Sprague-Dawley, Receptors, Cytoplasmic and Nuclear, Reverse Transcriptase Polymerase Chain Reaction, Steroidogenic Factor 1, Transcription Factors

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          Abstract

          Previously, we demonstrated that bone marrow-derived mesenchymal stem cells (MSCs) differentiate into steroidogenic cells such as Leydig and adrenocortical cells by the introduction of steroidogenic factor-1 (SF-1) and treatment with cAMP. In this study, we employed the same approach to differentiate umbilical cord blood (UCB)-derived MSCs. Despite UCB-MSCs differentiating into steroidogenic cells, they exhibited characteristics of granulosa-luteal-like cells. We found that peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) was expressed and further induced by cAMP stimulation in UCB-MSCs. Consistent with these results, tissue-specific expression of Pgc-1alpha was observed in rat ovarian granulosa cells. PGC-1alpha binds to the NR5A family [SF-1 and liver receptor homolog-1 (LRH-1)] of proteins and markedly enhances their transcriptional activities. Reporter assays revealed that PGC-1alpha activated the promoter activities of SF-1 and LRH-1 target genes. Infection of KGN cells (a human cell line derived from granulosa cells) with adenoviruses expressing PGC-1alpha resulted in the induction of steroidogenesis-related genes and stimulation of progesterone production. PGC-1alpha also induced SF-1 and LRH-1, with the latter induced to a greater extent. Knockdown of Pgc-1alpha in cultured rat granulosa cells resulted in attenuation of gene expression as well as progesterone production. Transactivation of the NR5A family by PGC-1alpha was repressed by Dax-1. PGC-1alpha binds to the activation function 2 domain of NR5A proteins via its consensus LXXLL motif. These results indicate that PGC-1alpha is involved in progesterone production in ovarian granulosa cells by potentiating transcriptional activities of the NR5A family proteins.

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          Journal
          20133449
          10.1210/me.2009-0352

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