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Molecular Cancer Research
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The Paradoxical Roles of Orphan Nuclear Receptor 4A (NR4A) in Cancer

Stephen Safe and Keshav Karki
Stephen Safe
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas.
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  • For correspondence: ssafe@cvm.tamu.edu
Keshav Karki
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas.
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DOI: 10.1158/1541-7786.MCR-20-0707 Published February 2021
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    Figure 1.

    Domain structure of NRs and similarities between NR4A1, NR4A2, and NR4A3.

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    Figure 2.

    Interactions of NR4A1 with cis-elements, DNA-bound RXR, and DNA-bound-Sp.

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    Figure 3.

    Basal and induced NR4A1 in blood-derived tumor—low expression of NR4A is observed in most blood-derived tumors due to promoter-paused RNA Pol II, and DHE induces NR4A tumor expression through recruitment of the super elongation complex (49). There is also evidence for cytoplasmic NR4A in some lymphomas (42) and the retinoid Fenretinimide also induced nuclear export of NR4A1, which formed a complex with bcl-2 (51).

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    Figure 4.

    NR4A-regulated pathway/gene expression in solid tumors. These results were derived primarily from knockdown studies (of NR4A1) and were observed in multiple cancer cell lines (55–59, 61, 63, 65, 71–75).

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    Figure 5.

    Drug/ligand/TGFβ-induced nuclear export of NR4A1 and mitochondrial/cytosolic interactions; various inputs are indicated (1–12) and resulting outputs are also illustrated as 1–12 (circled). NR4A1 ligands such as Celastrol and THPN also bind the receptor. The drug/agent-induced outputs illustrate the multiple interaction of extranuclear NR4A with mitochondrial targets as well as the endoplasmic reticulum and a proteasome complex.

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    Figure 6.

    Structures of ligands that bind NR4As. The KD values for receptor binding by cytosporone B (1.68 μmol/L; ref. 56), celastrol (292 nmol/L; ref. 133), and chloroquine (0.27 μmol/L; ref. 151) have been reported. KD values for prostaglandin A2 and CDIM12 have not been reported and the KD value for CDIM8 is 0.56 μmol/L (unpublished results).

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Molecular Cancer Research: 19 (2)
February 2021
Volume 19, Issue 2
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The Paradoxical Roles of Orphan Nuclear Receptor 4A (NR4A) in Cancer
Stephen Safe and Keshav Karki
Mol Cancer Res February 1 2021 (19) (2) 180-191; DOI: 10.1158/1541-7786.MCR-20-0707

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The Paradoxical Roles of Orphan Nuclear Receptor 4A (NR4A) in Cancer
Stephen Safe and Keshav Karki
Mol Cancer Res February 1 2021 (19) (2) 180-191; DOI: 10.1158/1541-7786.MCR-20-0707
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    • Abstract
    • Introduction
    • Role of NR4A in Blood-Derived Tumors
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Molecular Cancer Research
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