The Stress Response Mediator ATF3 Represses Androgen Signaling by Binding the Androgen Receptor

Abstract

f Activating transcription factor 3 (ATF3) is a common mediator of cellular stress response signaling and is often aberrantly expressed in prostate cancer. We report here that ATF3 can directly bind the androgen receptor (AR) and consequently repress AR-mediated gene expression. The ATF3-AR interaction requires the leucine zipper domain of ATF3 that independently binds the DNA-binding and ligand-binding domains of AR, and the interaction prevents AR from binding to cisacting elements required for expression of androgen-dependent genes while inhibiting the AR N-and C-terminal interaction. The functional consequences of the loss of ATF3 expression include increased transcription of androgen-dependent genes in prostate cancer cells that correlates with increased ability to grow in low-androgen-containing medium and increased proliferative activity of the prostate epithelium in ATF3 knockout mice that is associated with prostatic hyperplasia. Our results thus demonstrate that ATF3 is a novel repressor of androgen signaling that can inhibit AR functions, allowing prostate cells to restore homeostasis and maintain integrity in the face of a broad spectrum of intrinsic and environmental insults.

The Activating Transcription Factor 3 Protein Suppresses the Oncogenic Function of Mutant p53 Proteins

“…ATF3 also binds human papillomavirus E6 protein and activates p53 in human papillomavirus-positive cancer cells by blocking p53 ubiquitination (25). Moreover, ATF3 represses androgen signaling by binding to the androgen receptor in prostate cancer (26). These findings support a notion that ATF3 can regulate cancer development and progression via protein-protein interaction.…”

“…The construct expressing FLAG-p63 was obtained from Addgene (Cambridge, MA). Plasmids expressing ATF3 and ⌬ATF3 have been described previously (23,26). These genes were cloned into pIRES2-GFP (BD Biosciences) for bicistronic expression of ATF3 with GFP.…”

“…In vitro-translated proteins were then incubated with GST fusions immobilized onto glutathione-agarose at 4°C overnight. After extensive washes, bound proteins were resolved in SDS-polyacrylamide gels and detected by immunoblotting as described previously (26).…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…ATF3 reduces expression of tumor suppressor p53 and its downstream target genes in squamous cell carcinoma ) and transactivates expression of TGFβ genes in breast cancer (Yin et al 2010). In addition, ATF3 represses androgen-dependent genes by inhibiting androgen activity, resulting in prostate cancer development (Wang et al 2012a).…”

ATF3 Activates Stat3 Phosphorylation through Inhibition of p53 Expression in Skin Cancer Cells

“…ATF3 is expressed at low levels in normal cells but can be rapidly induced by multiple and diverse extracellular signals including growth factors, cytokines and some genotoxic stress agents Hai et al, 1999;Hai and Hartman, 2001;Fan et al, 2002;Taketani et al, 2012, Wang et al, 2012Lee et al, 2013). The physiological function of ATF3 has been addressed in several cell lines that ATF3 might be involved in homeostasis, wound healing, cell adhesion, cancer cell invasion, apoptosis and signaling pathways Wolfgang et al, 1997;Wolfgang et al, 2000;Allen-Jennings et al, 2001;Gold et al, 2012;Jang et al, 2012;Rose et al, 2012).…”