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Steroidogenic Factor 1 (NR5A1) Activates ATF3 Transcriptional Activity

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 rap...

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Autores principales: Emura, Natsuko, Wang, Chiung-Min, Yang, William Harry, Yang, Wei-Hsiung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073147/
https://www.ncbi.nlm.nih.gov/pubmed/32093223
http://dx.doi.org/10.3390/ijms21041429
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author Emura, Natsuko
Wang, Chiung-Min
Yang, William Harry
Yang, Wei-Hsiung
author_facet Emura, Natsuko
Wang, Chiung-Min
Yang, William Harry
Yang, Wei-Hsiung
author_sort Emura, Natsuko
collection PubMed
description 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.
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spelling pubmed-70731472020-03-19 Steroidogenic Factor 1 (NR5A1) Activates ATF3 Transcriptional Activity Emura, Natsuko Wang, Chiung-Min Yang, William Harry Yang, Wei-Hsiung Int J Mol Sci Article 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. MDPI 2020-02-20 /pmc/articles/PMC7073147/ /pubmed/32093223 http://dx.doi.org/10.3390/ijms21041429 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Emura, Natsuko
Wang, Chiung-Min
Yang, William Harry
Yang, Wei-Hsiung
Steroidogenic Factor 1 (NR5A1) Activates ATF3 Transcriptional Activity
title Steroidogenic Factor 1 (NR5A1) Activates ATF3 Transcriptional Activity
title_full Steroidogenic Factor 1 (NR5A1) Activates ATF3 Transcriptional Activity
title_fullStr Steroidogenic Factor 1 (NR5A1) Activates ATF3 Transcriptional Activity
title_full_unstemmed Steroidogenic Factor 1 (NR5A1) Activates ATF3 Transcriptional Activity
title_short Steroidogenic Factor 1 (NR5A1) Activates ATF3 Transcriptional Activity
title_sort steroidogenic factor 1 (nr5a1) activates atf3 transcriptional activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073147/
https://www.ncbi.nlm.nih.gov/pubmed/32093223
http://dx.doi.org/10.3390/ijms21041429
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AT yangwilliamharry steroidogenicfactor1nr5a1activatesatf3transcriptionalactivity
AT yangweihsiung steroidogenicfactor1nr5a1activatesatf3transcriptionalactivity