Abstract 3393: Nuclear receptor Nurr1 mediates cell proliferation and is involved in a p53-microRNA-34 regulatory network

Abstract

Nuclear receptor (NR) subfamily 4 member 2 (NR4A2), also known as Nurr1, has been shown to have oncogenic properties, in which it can mediate cell transformation, migration and drug resistance. However, the manner in which Nurr1 mediates these cancer-promoting features is not completely understood, but research implicates p53 as a potential intermediary. In this study, we show that Nurr1 enhances the proliferative rate of colorectal cancer cells. This increase in cell growth is accompanied by an upregulation of cyclin D3, a putative target gene of Nurr1. To understand how Nurr1 itself is regulated, we performed a reporter screen to identify microRNA regulators of Nurr1's 3’UTR. We identified miR-34c as a putative regulator of Nurr1 and this direct regulation was confirmed through site-directed mutagenesis of the predicted seed region. We next determined if p53 activation could affect Nurr1 expression through transcriptional activation of miR-34. Using Nutlin-3a to activate p53, we found that Nurr1 expression decreased in a dose response manner. Lastly, we sought to determine if Nurr1 could attenuate p53 activation. We found that overexpression of Nurr1 in colorectal cancer cells caused an attenuation of p53 transactivation of target genes following Nutlin-3a treatment. Our results suggest that a p53-miR-34-Nurr1 regulatory network exists, which would allow p53 to maintain Nurr1 in a suppressed state through miR-34-mediated regulation and prevent tumorigenesis. In cases of p53 mutation or Nurr1 overexpression, this network would be compromised, allowing Nurr1 to enhance tumorigenesis or drug resistance. Citation Format: Jordan A. Beard, Justin L. Hills, Alexa Tenga, Apana A. Takwi, Taosheng Chen. Nuclear receptor Nurr1 mediates cell proliferation and is involved in a p53-microRNA-34 regulatory network. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3393. doi:10.1158/1538-7445.AM2014-3393