Abstract
Steroidogenic Factor 1 (SF-1/NR5A1), an orphan nuclear receptor, is important for sexual differentiation and the development of multiple endocrine organs, as well as cell proliferation in cancer cells. Activating transcription factor 3 (ATF3) is a transcriptional repressor, and its expression is rapidly induced by DNA damage and oncogenic stimuli. Since both NR5A1 and ATF3 can regulate and cooperate with several transcription factors, we hypothesized that NR5A1 may interact with ATF3 and plays a functional role in cancer development. First, we found that NR5A1 physically interacts with ATF3. We further demonstrated that ATF3 expression is up-regulated by NR5A1. Moreover, the promoter activity of the ATF3 is activated by NR5A1 in a dose-dependent manner in several cell lines. By mapping the ATF3 promoter as well as the site-directed mutagenesis analysis, we provide evidence that NR5A1 response elements (−695 bp and −665 bp) are required for ATF3 expression by NR5A1. It is well known that the transcriptional activities of NR5A1 are modulated by post-translational modifications, such as small ubiquitin-related modifier (SUMO) modification and phosphorylation. Notably, we found that both SUMOylation and phosphorylation of NR5A1 play roles, at least in part, for NR5A1-mediated ATF3 expression. Overall, our results provide the first evidence of a novel relationship between NR5A1 and ATF3.
Highlights
Steroidogenic factor 1 (NR5A1) is an orphan nuclear receptor superfamily critical for regulation of sex determination, adrenal and gonadal development, reproductive function, and steroidogenesis [1,2,3,4]
Since NR5A1 cooperates with several transcription factors [14,15,36,37], we first analyzed whether NR5A1 can bind to Activating transcription factor 3 (ATF3)
To further investigate whether the ATF3 physically binds to NR5A1, HIS-FLAG-tagged ATF3 was expressed in the Y1 cells, which endogenously express NR5A1, and Ni2+-bead pull-down assay was performed
Summary
Steroidogenic factor 1 (NR5A1) ( called SF-1) is an orphan nuclear receptor superfamily critical for regulation of sex determination, adrenal and gonadal development, reproductive function, and steroidogenesis [1,2,3,4]. The majority of the transcription factors are regulated by post-translational modifications which are essential for normal physiological functions in cells. Small ubiquitin-related modifier (SUMO) modification is one type of post-translational modifications, and SUMOylation of transcription factors and nuclear receptors has a strong impact on their transcriptional activities [18,19,20]. Mounting evidence has demonstrated that NR5A1 can be SUMOylated on lysine 194 (K194, the major site) and lysine 119 (K119, the minor site), and SUMO modification of NR5A1 regulates its transcriptional activities [21,22,23,24].
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