NR4A nuclear receptors are orphans but not lonesome

Kurakula, Kondababu; Koenis, Duco S.; Tiel, Claudia M. van; Vries, Carlie J.M. de

doi:10.1016/j.bbamcr.2014.06.010

Cited by 128 publications

(129 citation statements)

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“…NR4A receptors have both unique and overlapping functions, and there is increasing evidence that they play an important role in cellular homeostasis and diseases associated with metabolism, cardiovascular and neurological functions, inflammation, and the immune system (38)(39)(40). Endogenous ligands for NR4A1 have not been identified; however, synthetic ligands that are structurally related to cytosporone B have been developed (41)(42)(43) and have potential clinical applications.…”

Section: Discussionmentioning

confidence: 99%

NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration

Hedrick

Lee

Doddapaneni

et al. 2016

Molecular and Cellular Biology

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cOverexpression of the nuclear receptor 4A1 (NR4A1) in breast cancer patients is a prognostic factor for decreased survival and increased metastasis, and this has been linked to NR4A1-dependent regulation of transforming growth factor ␤ (TGF-␤) signaling. Results of RNA interference studies demonstrate that basal migration of aggressive SKBR3 and MDA-MB-231 breast cancer cells is TGF-␤ independent and dependent on regulation of ␤1-integrin gene expression by NR4A1 which can be inhibited by the NR4A1 antagonists 1,1-bis(3=-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) and a related p-carboxymethylphenyl [1,1-bis(3=-indolyl)-1-(p-carboxymethylphenyl)methane (DIM-C-pPhCO 2 Me)] analog. The NR4A1 antagonists also inhibited TGF-␤-induced migration of MDA-MB-231 cells by blocking nuclear export of NR4A1, which is an essential step in TGF-␤-induced cell migration. We also observed that NR4A1 regulates expression of both ␤1-and ␤3-integrins, and unlike other ␤1-integrin inhibitors which induce prometastatic ␤3-integrin, NR4A1 antagonists inhibit expression of both ␤1-and ␤3-integrin, demonstrating a novel mechanism-based approach for targeting integrins and integrin-dependent breast cancer metastasis. Cell adhesion and attachment are essential for tissue integrity and cellular homeostasis, and the heterodimeric integrin cell surface receptors play a critical role in these processes (1-3). There are 18 different ␣ subunits and 8 different ␤ subunits that form 24 ␣␤-integrin receptor heterodimers, and the large 12-member ␤1-integrin subgroup bind multiple extracellular matrix (ECM) molecules to activate multiple intracellular pathways and also induce cross talk with other signaling systems (1-3). The functions of integrin heterodimers are highly tissue specific, and many human pathologies also involve integrin signaling (reviewed in references 4 and 5). ␤1-Integrin is highly expressed in most tumors and is associated with a negative prognostic significance such as overall and disease-free survival, recurrence, and metastasis for head and neck and squamous cell carcinoma, melanoma, lung, breast, prostate, laryngeal, and pancreatic cancers (6-17). A recent immunostaining study of 225 breast invasive ductal carcinomas (IDCs) showed that ␤1-integrin was overexpressed in 32.8% of patients with IDCs (13). Numerous studies show that focal adhesion kinase (FAK) which is downstream from ␤1-integrin is also a negative prognostic factor for breast cancer patients (18)(19)(20). The important functional role of ␤1-integrin has been demonstrated in mouse models expressing erbB2 under the control of the mouse mammary tumor virus and crossed with mammary tissue-specific ␤1-integrin-deficient mice. These mice exhibit a decrease in tumor volume, increased apoptosis, and decreased lung metastasis compared to animals expressing wild-type ␤1-integrin (21-23). Although small molecules, peptides, and antibodies that inhibit ␤1-integrin signaling have been developed, clinical agents that target ␤1-integrin for cancer chemotherapy are not cur...

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Section: Discussionmentioning

confidence: 99%

NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration

Hedrick

Lee

Doddapaneni

et al. 2016

Molecular and Cellular Biology

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“…Ligands for Nr4a1, Nr4a2, and Nr4a3 are not yet known; thus, these receptors are classified as orphan receptors. 85 The roles of NGFIB in T cells have been recently recognized in the context of Th17 and Treg subsets, similar to many other nuclear receptors. Nr4a1 is essential for the clonal deletion of thymocytes and the development of Tregs in mice.…”

Section: Aryl Hydrocarbon Receptor (Ahr)mentioning

confidence: 99%

The role of nuclear receptors in regulation of Th17/Treg biology and its implications for diseases

Park

Fan

2015

Cell Mol Immunol

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Nuclear receptors in the cell play essential roles in environmental sensing, differentiation, development, homeostasis, and metabolism and are thus highly conserved across multiple species. The anti-inflammatory role of nuclear receptors in immune cells has recently gained recognition. Nuclear receptors play critical roles in both myeloid and lymphoid cells, particularly in helper CD41 T-cell type 17 (Th17) and regulatory T cells (Treg). Th17 and Treg are closely related cell fates that are determined by orchestrated cytokine signaling. Recent studies have emphasized the interactions between nuclear receptors and the known cytokine signals and how such interaction affects Th17/Treg development and function. This review will focus on the most recent discoveries concerning the roles of nuclear receptors in the context of therapeutic applications in autoimmune diseases.

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“…Interaction regions of protein kinases, transcription factors and transcriptional co-regulators are also indicated (e.g. multiple phosphorylation sites in NR4A1 were identified within the TAD and DBD) [13]. Fig.…”

Section: Nr4a1 and Apoptosismentioning

confidence: 99%

“…Due to the presence of several closely packed hydrophobic amino acid residues in the LBD, there is no ligandbinding pocket allowing interaction with possible ligands [9,10]. Therefore, regulation of protein activity is probably ligand-independent and occurs at the level of both gene transcription and post-translational modifications [3,[11][12][13].…”

mentioning

confidence: 97%