論文 - 詳細
| RRC ID | 85425 |
|---|---|
| 著者 | Kalyanaraman H, Casteel DE, China SP, Zhuang S, Boss GR, Pilz RB. |
| タイトル | A plasma membrane-associated form of the androgen receptor enhances nuclear androgen signaling in osteoblasts and prostate cancer cells. |
| ジャーナル | Sci Signal |
| Abstract |
Androgen binding to the androgen receptor (AR) in the cytoplasm induces the AR to translocate to the nucleus, where it regulates the expression of target genes. Here, we found that androgens rapidly activated a plasma membrane-associated signaling node that enhanced nuclear AR functions. In murine primary osteoblasts, dihydrotestosterone (DHT) binding to a membrane-associated form of AR stimulated plasma membrane-associated protein kinase G type 2 (PKG2), leading to the activation of multiple kinases, including ERK. Phosphorylation of AR at Ser515 by ERK increased the nuclear accumulation and binding of AR to the promoter of Ctnnb1, which encodes the transcription factor β-catenin. In male mouse osteoblasts and human prostate cancer cells, DHT induced the expression of Ctnnb1 and CTNN1B, respectively, as well as β-catenin target genes, stimulating the proliferation, survival, and differentiation of osteoblasts and the proliferation of prostate cancer cells in a PKG2-dependent fashion. Because β-catenin is a master regulator of skeletal homeostasis, these results explain the reported male-specific osteoporotic phenotype of mice lacking PKG2 in osteoblasts and imply that PKG2-dependent AR signaling is essential for maintaining bone mass in vivo. Our results suggest that widely used pharmacological PKG activators, such as sildenafil, could be beneficial for male and estrogen-deficient female patients with osteoporosis but detrimental in patients with prostate cancer. |
| 巻・号 | 17(821) |
| ページ | eadi7861 |
| 公開日 | 2024-1-30 |
| DOI | 10.1126/scisignal.adi7861 |
| PMID | 38289986 |
| PMC | PMC10916501 |
| MeSH | Androgens* / metabolism Androgens* / pharmacology Animals Cell Line, Tumor Cell Membrane / metabolism Dihydrotestosterone / metabolism Dihydrotestosterone / pharmacology Humans Male Mice Osteoblasts Prostatic Neoplasms* / genetics Prostatic Neoplasms* / metabolism Receptors, Androgen / genetics Receptors, Androgen / metabolism beta Catenin / genetics beta Catenin / metabolism |
| IF | 6.467 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 10 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 実験動物マウス | RBRC05524 |