TY - JOUR

T1 - Orphan receptor NR4A3 is a novel target of p53 that contributes to apoptosis

AU - Fedorova, Olga

AU - Petukhov, Alexey

AU - Daks, Alexandra

AU - Shuvalov, Oleg

AU - Leonova, Tatyana

AU - Vasileva, Elena

AU - Aksenov, Nikolai

AU - Melino, Gerry

AU - Barlev, Nikolai A.

N1 - Funding Information: Acknowledgements O.F., A.P. and E.V. carried out chromatin immunoprecipitation, Luciferase assay, quantitative PCR, cell-cycle analysis, colony formation assay, immunofluorescence, wound-healing and real-time cell migration assay and acknowledge the support from RCF grant 18-75-10076. A.D., O.S., N.B. carried out annexin V, co-immunoprecipitation interaction assay and the bioinformatics analysis and acknowledge the support from RFBR grant 18-29-09144. We appreciate Dr Mikhal Maliewitz (MRC Toxicology, Leicester) for a gift of NR4A1 and NR4A2 antibodies. Publisher Copyright: © 2018, Springer Nature Limited. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/3/21

Y1 - 2019/3/21

N2 - Major tumor suppressor and transcription factor p53 coordinates expression of many genes hence affecting critical cellular functions including cell cycle, senescence, and apoptosis. The NR4A family of orphan receptors (NR4A1-3) belongs to the superfamily of nuclear receptors. They regulate genes involved in proliferation, cell migration, and apoptosis. In this study, we report an identification of NR4A3 as a direct transcriptional target of p53. Using various techniques, we showed that p53 directly bound the promoter of NR4A3 gene and induced its transcription. Functionally, over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax. Knockdown of NR4A3 reversed these phenotypes. Importantly, NR4A3 exhibited tumor suppressive functions both in p53-dependent and independent manner. In addition, NR4A3 physically interacted with an anti-apoptotic Bcl-2 protein hence sequestering it from blunting apoptosis. These observations were corroborated by the bioinformatics analysis, which demonstrated a correlation between high levels of NR4A3 expression and better survival of breast and lung cancer patients. Collectively, our studies revealed a novel transcriptional target of p53, NR4A3, which triggers apoptosis and thus likely has a tumor suppressive role in breast and lung cancers.

AB - Major tumor suppressor and transcription factor p53 coordinates expression of many genes hence affecting critical cellular functions including cell cycle, senescence, and apoptosis. The NR4A family of orphan receptors (NR4A1-3) belongs to the superfamily of nuclear receptors. They regulate genes involved in proliferation, cell migration, and apoptosis. In this study, we report an identification of NR4A3 as a direct transcriptional target of p53. Using various techniques, we showed that p53 directly bound the promoter of NR4A3 gene and induced its transcription. Functionally, over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax. Knockdown of NR4A3 reversed these phenotypes. Importantly, NR4A3 exhibited tumor suppressive functions both in p53-dependent and independent manner. In addition, NR4A3 physically interacted with an anti-apoptotic Bcl-2 protein hence sequestering it from blunting apoptosis. These observations were corroborated by the bioinformatics analysis, which demonstrated a correlation between high levels of NR4A3 expression and better survival of breast and lung cancer patients. Collectively, our studies revealed a novel transcriptional target of p53, NR4A3, which triggers apoptosis and thus likely has a tumor suppressive role in breast and lung cancers.

UR - http://www.scopus.com/inward/record.url?scp=85056826185&partnerID=8YFLogxK

U2 - 10.1038/s41388-018-0566-8

DO - 10.1038/s41388-018-0566-8

M3 - Article

C2 - 30455429

AN - SCOPUS:85056826185

VL - 38

SP - 2108

EP - 2122

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 12

ER -