Androgens Regulate Ovarian Gene Expression Through Modulation of Ezh2 Expression and Activity
| Autor: | Stephen R. Hammes, Emily Hayes, Anindita Biswas, Christina Seger, Aritro Sen, Xiaoting Ma, Hen Prizant |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty medicine.drug_class Gene Expression Mice Transgenic 030209 endocrinology & metabolism macromolecular substances Biology Mice Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Endocrinology Transcription (biology) Internal medicine microRNA Gene expression medicine Animals Humans Enhancer of Zeste Homolog 2 Protein Phosphorylation Transcription factor Cells Cultured Research Articles PI3K/AKT/mTOR pathway Ovary Promoter Androgen Cell biology Mice Inbred C57BL Oncogene Protein v-akt Androgen receptor MicroRNAs 030104 developmental biology Androgens Female Signal Transduction |
| Zdroj: | Endocrinology. 158:2944-2954 |
| ISSN: | 1945-7170 0013-7227 |
| Popis: | A substantial amount of evidence suggests that androgen signaling through classical androgen receptors is critical for both normal and pathologic ovarian physiology. Specifically, we and others have shown that, in mouse granulosa cells, androgen actions through both extranuclear and nuclear androgen receptor signaling are critical for normal follicle development and ovulation. Here, we show that androgens through the PI3K/Akt pathway rapidly (within minutes) phosphorylate and inhibit activity of the Polycomb group protein enhancer of zeste homolog 2 (Ezh2). Over the course of 24 to 48 hours, androgens then induce expression of the microRNA miR-101, which targets Ezh2 messenger RNA (mRNA), leading to a nearly complete loss of Ezh2 protein expression. This long-term androgen-induced loss of Ezh2 actions ultimately results in sustained reduction of the H3K27me3-repressive mark in the promoter region of the Runt-related transcription factor-1 (Runx1) gene, a luteinizing hormone (LH)–induced transcription factor essential for ovulation, leading to increased Runx1 mRNA expression. Accordingly, blocking androgen-induced inhibition of Ezh2 in vivo adversely affects LH-induced Runx1 mRNA expression and subsequent ovulation. Importantly, although estrogen treatment of granulosa cells similarly causes rapid activation of the PI3K/Akt pathway and short-term phosphorylation of Ezh2, it does not induce miR-101 expression and thereby does not reduce overall Ezh2 expression, demonstrating the androgen specificity of long-term Ezh2 suppression. Thus, this study provides insight regarding how androgen-induced extranuclear kinase signaling and intranuclear transcription through Ezh2 modifications may influence the expression pattern of genes, ultimately affecting various downstream physiological processes. |
| Databáze: | OpenAIRE |
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