Androgen receptor activation integrates complex transcriptional effects in osteoblasts, involving the growth factors TGF-β and IGF-I, and transcription factor C/EBPδ
| Autor: | Thomas L. McCarthy, Michael Centrella |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
CCAAT-Enhancer-Binding Protein-delta
endocrine system Transcription Genetic Response element SMAD Biology Rats Sprague-Dawley Transactivation Transforming Growth Factor beta Genetics medicine Animals Insulin-Like Growth Factor I Promoter Regions Genetic Transcription factor Cells Cultured Bone growth Osteoblasts Promoter General Medicine Cell biology Rats Androgen receptor Receptors Androgen Dihydrotestosterone Cancer research hormones hormone substitutes and hormone antagonists medicine.drug |
| Zdroj: | Gene. 573(1) |
| ISSN: | 1879-0038 |
| Popis: | Osteoblasts respond to many growth factors including IGF-I and TGF-β, which themselves are sensitive to other bone growth regulators. Here we show that IGF-I gene promoter activity in prostaglandin E2 (PGE2) induced osteoblasts is suppressed by dihydrotestosterone (DHT) through an essential C/EBP response element (RE) in exon 1 of the igf1 gene. Inhibition by DHT fails to occur when the androgen receptor (AR) gene is mutated within its DNA binding domain. Correspondingly, DHT activated AR inhibits gene transactivation by C/EBPδ, and transgenic C/EBPδ expression inhibits AR activity. Inhibition by DHT persists when upstream Smad and Runx REs in the IGF-I gene promoter are mutated. TGF-β also enhances IGF-I gene promoter activity, although modestly relative to PGE2, and independently of the C/EBP, Smad, or Runx REs. Still, DHT suppresses TGF-β induced IGF-I promoter activity, but not its effects on DNA or collagen synthesis. Notably, DHT suppresses plasminogen activator inhibitor gene promoter activity, but synergistically increases Smad dependent gene promoter activity in TGF-β induced cells, which are differentially sensitive to AR mutations and the AR co-regulator ARA55. Finally, although the PGE2 sensitive C/EBP RE in the igf1 gene is not essential for basal TGF-β induction, C/EBPδ activity through this site is potently enhanced by TGF-β. Thus DHT suppresses the PGE2 and TGF-β induced IGF-I gene promoter and differentiates other aspects of TGF-β activity in osteoblasts. Our results extend the complex interactions among local and systemic bone growth regulators to DHT, and predict complications from anabolic steroid use in other DHT sensitive tissues. |
| Databáze: | OpenAIRE |
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