Abstract
Androgen receptor (AR) belongs to the steroid hormone nuclear receptor superfamily. It functions as an androgen-dependent transcriptional factor that regulates genes for cell proliferation and differentiation. Caveolin is a principal component of caveolae membranes serving as a scaffold protein of many signal transduction pathways. Recent results correlate caveolin-1 expression with androgen sensitivity in murine prostate cancer. Furthermore, immunohistochemical staining of patient specimens suggests that caveolin expression may be an independent predictor of progression of prostate cancer. In this study, we investigate the potential interactions between AR signaling and caveolin-1 and demonstrate that overexpression of caveolin-1 potentiates ligand-dependent AR activation. Conversely, down-regulation of caveolin-1 expression by a caveolin-1 antisense expression construct can down-regulate ligand-dependent AR activation. Association between these two molecules is also demonstrated by co-localization of AR with caveolin-rich, low-density membrane fractions isolated by an equilibrium sucrose gradient centrifugation method. Co-immunoprecipitation and glutathione S-transferase fusion protein pull-down experiments demonstrate that interaction between AR and caveolin-1 is an androgen-dependent process, offering further evidence for a physiological role of this interaction. Using a mammalian two-hybrid assay system, we determine that the NH(2) terminus region of caveolin-1 is responsible for the interaction with both the NH(2)-terminal domain and the ligand-binding domain of AR.
Highlights
Androgen receptor (AR) belongs to the steroid hormone nuclear receptor superfamily
We demonstrate an association between these two molecules by finding co-localization of AR with caveolin-rich, low-density membrane fractions isolated by an equilibrium sucrose gradient centrifugation method
Overexpression of Caveolin-1 Enhances AR-mediated Transcriptional Activity and Increases the Sensitivity of AR to Liganddependent Activation—High levels of caveolin-1 expression have been observed to correlate with the sensitivity of murine metastatic prostate cancer cells to androgen withdrawal [12], a finding that suggests caveolin plays a role in AR signaling
Summary
Down-regulation of caveolin-1 expression by a caveolin-1 antisense expression construct can downregulate ligand-dependent AR activation Association between these two molecules is demonstrated by co-localization of AR with caveolin-rich, low-density membrane fractions isolated by an equilibrium sucrose gradient centrifugation method. Androgen receptor (AR) belongs to the steroid hormone nuclear receptor superfamily It functions as a ligand-dependent transcriptional factor that regulates genes for cell proliferation and differentiation. Other nongrowth factor-related signal pathways reported to modulate AR include protein kinase A, which mediates ligand-independent AR activation [6, 7], and protein kinase C, which negatively regulates AR-dependent transcription [8]. Nongenomic estradiol stimulation of nitric oxide release has been shown to be mediated by estrogen receptors localized in caveolae [28] In light of these findings, we investigate the potential interactions between AR signaling and caveolin-1. Using a mammalian two-hybrid assay system, we determine that the caveolin-1 NH2 terminus region is responsible for the interaction with both the NH2-terminal domain and the ligand-binding domain (LBD) of AR
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