The nuclear receptor nr4a1 controls CD8 T cell development through transcriptional suppression of runx3.
Ontology highlight
ABSTRACT:
SUBMITTER: Nowyhed HN
PROVIDER: S-EPMC4356985 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A 4.1 μs molecular dynamics simulation of the NR4A1 (hNur77) apo-protein has been undertaken and a previously undetected druggable pocket has become apparent that is located remotely from the 'traditional' nuclear receptor ligand-binding site. A NR4A1/bis-indole ligand complex at this novel site has been found to be stable over 1 μs of simulation and to result in an interesting conformational transmission to a remote loop that has the capacity to communicate with a NBRE within a RXR-α/NR4A1 heterodimer. Several features of the simulations undertaken indicate how NR4A1 can be affected by alternate-site modulators.
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Project description:Resveratrol is a polyphenolic phytochemical found in fruits, nuts and vegetables that contributes to the remarkable dietary effects of polyphenolic as inhibitors aging and multiple aging related diseases. In addition, resveratrol has been extensively investigated as an inhibitor of inflammatory diseases including cancer, however, the underlying mechanisms of these chemotherapeutic effects of resveratrol are not completely understood. In cancer cells resveratrol inhibits cell growth, survival, migration and invasion, and many of the effects of resveratrol resemble those observed for bis-indole derived (CDIM) compounds that bind the pro-oncogenic nuclear receptor 4A1 (NR4A1, Nur77) and act as receptor antagonists. Using an isothermal titration calorimetry binding assay, we observed that resveratrol bound to the ligand binding domain of NR4A1 with a KD value of 2.4 µM and a ΔG of -32.2 kJ/mol. Resveratrol also inhibited NR4A1-dependent transactivation in H460 and H1299 lung cancer cells suggesting that resveratrol is an NR4A1 antagonist. This observation was confirmed in a series of functional (cell proliferation, survival, migration and invasion) and gene expression assays in H460 and H1299 cells showing that treatment with resveratrol mimicked the effects of NR4A1 knockdown and were similar to results of previous studies using CDIM/NR4A1 antagonists. These data indicate that applications of resveratrol may be more effective in patients that overexpress NR4A1 which is a negative prognostic factor for patients with some solid tumor-derived cancers. Significance Statement We have examined the mechanism of action of resveratrol and show binding to NR4A1 (KD = 2.4 µM) and inhibition of NR4A1-dependent transactivation in lung cancer cells. Treatment of H460 and H1299 lung cancer cells with resveratrol inhibits cell growth, survival, migration/invasion and related genes, and acts as an NR4A1 antagonist. Resveratrol can now be used more effectively in cancer chemotherapy by targeting patients that overexpress NR4A1 in lung cancer.
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Project description:The RUNX transcription factors are important regulators of lineage-specific gene expression. RUNX are bifunctional, acting both as activators and repressors of tissue-specific target genes. Recently, we have demonstrated that Runx3 is a neurogenic transcription factor, which regulates development and survival of proprioceptive neurons in dorsal root ganglia. Here we report that Runx3 and Runx1 are highly expressed in thymic medulla and cortex, respectively, and function in development of CD8 T cells during thymopoiesis. Runx3-deficient (Runx3 KO) mice display abnormalities in CD4 expression during lineage decisions and impairment of CD8 T cell maturation in the thymus. A large proportion of Runx3 KO peripheral CD8 T cells also expressed CD4, and in contrast to wild-type, their proliferation ability was largely reduced. In addition, the in vitro cytotoxic activity of alloimmunized peritoneal exudate lymphocytes was significantly lower in Runx3 KO compared with WT mice. In a compound mutant mouse, null for Runx3 and heterozygous for Runx1 (Runx3-/-;Runx1+/-), all peripheral CD8 T cells also expressed CD4, resulting in a complete lack of single-positive CD8+ T cells in the spleen. The results provide information on the role of Runx3 and Runx1 in thymopoiesis and suggest that both act as transcriptional repressors of CD4 expression during T cell lineage decisions.
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2014-06-01 | E-GEOD-48782 | biostudies-arrayexpress
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