The orphan nuclear receptor NR4A2 is part of a p53-microRNA-34 network.
Nuclear receptor subfamily 4 group A member 2 (NR4A2) is an orphan nuclear receptor that is over-expressed in cancer and promotes cell proliferation, migration, transformation, and chemoresistance. Increased expression and function of NR4A2 have been attributed to various signaling pathways, but little is known about microRNA (miRNA) regulation of NR4A2 in cancer. To investigate the posttranscriptional regulation of NR4A2, we used a 3' untranslated region (UTR) reporter screen and identified miR-34 as a putative regulator of NR4A2. By using computer predictions, we identified and confirmed an miRNA recognition element in the 3' UTR of NR4A2 that was responsible for miR-34-mediated suppression. We next demonstrated that overexpression of exogenous miR-34 or activation of the p53 pathway, which regulates endogenous miR-34 expression, decreased NR4A2 expression. Consistent with previous reports, overexpression of NR4A2 blocked the induction of p53 target genes, including mir-34a. This was a phenotypic effect, as NR4A2 overexpression could rescue cells from p53-induced inhibition of proliferation. In summary, our results are the first characterization of a cancer-related miRNA capable of regulating NR4A2 and suggest a network and possible feedback mechanism involving p53, miR-34, and NR4A2.
Department of Chemical Biology &Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Jordan A
JA
Beard
Department of Chemical Biology &Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Alexa
A
Tenga
Department of Chemical Biology &Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Justin
J
Hills
Department of Chemical Biology &Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Jessica D
JD
Hoyer
Department of Chemical Biology &Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Milu T
MT
Cherian
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Yong-Dong
YD
Wang
Department of Chemical Biology &Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Taosheng
T
Chen
D020413:3' Untranslated Regions; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D020413:3' Untranslated Regions; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D057093:Orphan Nuclear Receptors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53