Androgen receptor stimulates bone sialoprotein (BSP) gene transcription via cAMP response element and activator protein 1/glucocorticoid response elements

Abstract

Bone sialoprotein (BSP) is an early marker of osteoblast differentiation. Androgens are steroid hormones that are essential for skeletal development. The androgen receptor (AR) is a transcription factor and a member of the steroid receptor superfamily that plays an important role in male sexual differentiation and prostate cell proliferation. To determine the molecular mechanism involved in the stimulation of bone formation, we have analyzed the effects of androgens and AR effects on BSP gene transcription. AR protein levels were increased after AR overexpression in ROS17/2.8 cells. BSP mRNA levels were increased by AR overexpression. However, the endogenous and overexpressed BSP mRNA levels were not changed by DHT (10(-8) M, 24 h). Whereas luciferase (LUC) activities in all constructs, including a short construct (nts -116 to +60), were increased by AR overexpression, the basal and LUC activities enhanced by AR overexpression were not induced by DHT (10(-8)M, 24 h). The effect of AR overexpression was abrogated by 2 bp mutations in either the cAMP response element (CRE) or activator protein 1 (AP1)/glucocorticoid response element (GRE). Gel shift analyses showed that AR overexpression increased binding to the CRE and AP1/GRE elements. Notably, the CRE-protein complexes were supershifted by phospho-CREB antibody, and CREB, c-Fos, c-Jun, and AR antibodies disrupted the complexes formation. The AP1/GRE-protein complexes were supershifted by c-Fos antibody and c-Jun, and AR antibodies disrupted the complexes formation. These studies demonstrate that AR stimulates BSP gene transcription by targeting the CRE and AP1/GRE elements in the promoter of the rat BSP gene.

Differential expression of angiogenesis associated genes in prostate cancer bone, liver and lymph node metastases

“…The expression of bone sialoprotein in the PCa cells may be coordinated and regulated through a cAMP-dependent PKA signaling pathway [24]. The androgen receptor has also been suggested to stimulate bone sialoprotein gene transcription via a cAMP response element [25]. The increased expression of bone sialoprotein in the bone microenvironment shows our results are in concordance with previously published results.…”

Small-Molecule Hormones: Molecular Mechanisms of Action

“…Binding of the steroid hormone receptor to SRE initiates recruitment of a multiprotein coactivator complex which, by modification of chromatin structure (e.g., histone acetylation by histone acetyltransferases, HATs) and by interaction with the basal transcriptional machinery, activates transcription [135–140] (Figure 3). In addition, steroid hormones acting by their nuclear receptors can potentiate the transactivatory function of other transcription factors [141–143]. …”

Osthole Enhances Osteogenesis in Osteoblasts by Elevating Transcription Factor Osterix via cAMP/CREB Signaling In Vitro and In Vivo

“…It leads to the activation of protein kinase A (PKA) and phosphorylation of the cAMP response element-binding protein (CREB) [27,30]. Activated CREB binds to the cAMP response element (CRE) and triggers the cascade expression of osteogenic-related genes [31,32]. Osthole was reported to elevate cAMP levels in adrenocortical cancer cells, trachea, and corpus cavernosum tissues [33,34,35].…”