In this study, we investigated the role of Nur77, an orphan nuclear receptor, in HIF-α transcriptional activity. We found that Nur77 associates and stabilizes HIF-1α via indirect interaction. Nur77 was found to interact with pVHL in vivo via the α-domain of pVHL. By binding to pVHL, Nur77 competed with elongin C for pVHL binding. Moreover, Nur77-binding to pVHL inhibited the pVHL-mediated ubiquitination of HIF-1α and ultimately increased the stability and transcriptional activity of HIF-1α. The ligand-binding domain of Nur77 was found to interact with pVHL and the expression of this ligand-binding domain was sufficient to stabilize and transactivate HIF-1α. Under the conditions that cobalt chloride was treated or pVHL was knocked down, Nur77 could not stabilize HIF-α. Moreover, Nur77 could not further stabilize HIF-2α in A498/VHL stable cells, which is consistent with our finding that Nur77 indirectly stabilizes HIF-α by binding to pVHL. Thus, our results suggest that an orphan nuclear receptor Nur77 binds to pVHL, thereby stabilizes and increases HIF-α transcriptional activity under the nonhypoxic conditions.
TCR signaling leading to thymocyte apoptosis is mediated through the expression of the Nur77 family of orphan nuclear receptors. It has been shown that the Nur77 promoter is activated by at least two signaling pathways, one mediated by calcium and the other by protein kinase C (PKC). MEF2D has been known to regulate Nur77 expression in a calciumdependent manner. The mechanism by which calcium regulates MEF2D is through dissociation of calcium-sensitive MEF2 corepressors (Cabin1/ HDACs, HDAC4/5) and the association with calcineurin-activated transcription factor NF-AT and the coactivator p300. However, little is known about how PKC activates the Nur77 promoter. Herein, we report that PKC targets AP-1 like response element in the Nur77 promoter where JunD constitutively binds. PKCθ triggers mitogen-activated protein kinaseinediated phosphorylation of JunD, and increases transcriptional activity of JunD, cooperatively with p300. Menin is identified as the transcriptional corepressor for JunD via recruitment of mSin3-istone deacetylases. In fact, Menin represses PKCθ/ p300-mediated transcriptional activity of JunD in T cell. Its dynamic regulation of histone modifiers with JunD is responsible for PKCθ-synergistic effect on Nur77 expression in T cell.
This study was conducted to investigate the effects of selenium feeding and supplementation in diet on the concentration of selenium in blood and velvet antler of spotted deer (Sika deer). Three spotted deer were fed high selenium concentration (6 mg/kg DM). Absorption and retention rates of selenium were examined by evaluating selenium concentrations in feces and urine. Stress-related hormones and serum biochemical parameters in blood were also evaluated for the purpose of detecting any negative effect by the high level of selenium feeding. Eight spotted deers were randomly assigned to two groups and were fed with one of two diets for 20 days, which were with or without the addition of 6 mg selenium /kg diet. Concentration of selenium in velvet antler was evaluated. Selenium concentration in blood of spotted deer fed high level selenium for 30 days was significantly increased (p<0.05), retention rate of selenium reached 59.15%. No differences in level of stress-related hormone and biochemical parameters (NEFA, ALT, AST) in blood were observed by feeding high level selenium. The diet with selenium significantly increased concentrations of selenium in top (0.11 vs 0.45 ppm; p<0.001), middle (0.08 vs 0.21 ppm; p<0.01) and basepart (0.08 vs 0.15 ppm; p<0.05) of velvet antler.
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