A critical role for the co-repressor N-CoR in erythroid differentiation and heme synthesis

Zhang, Dianzheng; Cho, Ellen; Wong, Jiemin

doi:10.1038/cr.2007.72

Cited by 27 publications

(17 citation statements)

References 48 publications

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“…To elucidate whether α-toxin impairs the differentiation of human erythroid progenitors, we treated K562 human erythroleukemia cells with α-toxin while inducing the differentiation of cells using hemin, and monitored the erythroid differentiation by measuring hemoglobin production. As described previously 20 , hemin increased the production of hemoglobin, demonstrating that the compound induces erythroid differentiation of K562 cells (Fig. 5A).…”

Section: Resultssupporting

confidence: 86%

“…The cells were cultured in RPMI 1640 medium supplemented with 10% FBS, 100 units/ml penicillin, and 100 µg/ml streptomycin in a humidified atmosphere of 95% air with 5% CO 2 at 37 °C. To induce the differentiation of K562 cells, the cells were cultured for 3–6 days in the presence of hemin, and hemoglobin synthesis in the cells was determined as reported previously 20 . Briefly, the cells were washed with cold PBS and suspended in lysis buffer (100 mM potassium phosphate pH 7.8, 0.2% Triton X-100).…”

Section: Methodsmentioning

confidence: 99%

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Clostridium perfringens α-toxin impairs erythropoiesis by inhibition of erythroid differentiation

Takagishi

Takehara

Seike

et al. 2017

Sci Rep

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Clostridium perfringens α-toxin induces hemolysis of erythrocytes from various species, but it has not been elucidated whether the toxin affects erythropoiesis. In this study, we treated bone marrow cells (BMCs) from mice with purified α-toxin and found that TER119 + erythroblasts were greatly decreased by the treatment. A variant α-toxin defective in enzymatic activities, phospholipase C and sphingomyelinase, had no effect on the population of erythroblasts, demonstrating that the decrease in erythroblasts was dependent of its enzymatic activities. α-Toxin reduced the CD71 + TER119 + and CD71 -TER119 + cell populations but not the CD71 + TER119 − cell population. In addition, α-toxin decreased the number of colony-forming unit erythroid colonies but not burst-forming unit erythroid colonies, indicating that α-toxin preferentially reduced mature erythroid cells compared with immature cells. α-Toxin slightly increased annexinV + cells in TER119 + cells. Additionally, simultaneous treatment of BMCs with α-toxin and erythropoietin greatly attenuated the reduction of TER119 + erythroblasts by α-toxin. Furthermore, hemin-induced differentiation of human K562 erythroleukemia cells was impaired by α-toxin, whereas the treatment exhibited no apparent cytotoxicity. These results suggested that α-toxin mainly inhibited erythroid differentiation. Together, our results provide new insights into the biological activities of α-toxin, which might be important to understand the pathogenesis of C. perfringens infection.Clostridium perfringens α-toxin, which is a major virulence factor during C. perfringens infection, is known to have two enzyme activities, phospholipase C (PLC) and sphingomyelinase (SMase), and these activities has been shown to be involved in various biological activities 1, 2 . Previously, it was reported that the toxin caused the contraction of rat ileum and aorta by activating phosphatidylinositol turnover and the production of thromboxane A 2 , respectively 3-5 . The toxin reduced skeletal muscle blood flow through thrombosis by promoting the aggregation of activated platelets and leukocytes, which caused the rapid destruction of skeletal muscle [6][7][8] . In addition, α-toxin has been reported to directly disrupt cell membrane and cause cytolysis 9-11 . These biological activities are proposed to play major roles in C. perfringens-induced myonecrosis. Recently, we reported that α-toxin inhibits neutrophil differentiation to impair the innate immune system by perturbing the integrity of lipid rafts in neutrophils 12, 13 . Thus, α-toxin affects a broad range of cell lines and induces various biological activities that are important to understand the pathogenesis of C. perfringens infection.C. perfringens α-toxin is also known to induce the hemolysis of various erythrocytes. We reported that the toxin activated the sphingomyelin metabolic system leading to the hemolysis of sheep erythrocytes 14,15 . Additionally, we reported previously that α-toxin activated endogenous PLC leading to the hemolysis of rabbit ...

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Section: Resultssupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Clostridium perfringens α-toxin impairs erythropoiesis by inhibition of erythroid differentiation

Takagishi

Takehara

Seike

et al. 2017

Sci Rep

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“…After 10 min of incubation at room temperature, benzidine-positive cells were counted under the microscope with a minimum of 200 cells scored. Second, to define the relative content of hemoglobin spectrophotometrically [51], equal number of cells (7×10 6 ) were washed with cold PBS and lysed for 20 min in 100 µl of lysis buffer (0.2% Triton X-100 in 100 mM potassium phosphate buffer, pH 7.8). The lysates were centrifuged for 15 min at 1500 r.p.m.…”

Section: Methodsmentioning

confidence: 99%

Products of Vitamin D3 or 7-Dehydrocholesterol Metabolism by Cytochrome P450scc Show Anti-Leukemia Effects, Having Low or Absent Calcemic Activity

et al. 2010

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BackgroundCytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH)2D3, as well as 1-hydroxyvitamin D3 to 1α,20-dihydroxyvitamin D3 (1,20(OH)2D3). It also cleaves the side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL).Methods and FindingsTo define the biological significance of these P450scc-initiated pathways, we tested the effects of their 5,7-diene precursors and secosteroidal products on leukemia cell differentiation and proliferation in comparison to 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). These secosteroids inhibited proliferation and induced erythroid differentiation of K562 human chronic myeloid and MEL mouse leukemia cells with 20(OH)D3 and 20,23(OH)2D3 being either equipotent or slightly less potent than 1,25(OH)2D3, while 1,20(OH)2D3, pD and pL compounds were slightly or moderately less potent. The compounds also inhibited proliferation and induced monocytic differentiation of HL-60 promyelocytic and U937 promonocytic human leukemia cells. Among them 1,25(OH)2D3 was the most potent, 20(OH)D3, 20,23(OH)2D3 and 1,20(OH)2D3 were less active, and pD and pL compounds were the least potent. Since it had been previously proven that secosteroids without the side chain (pD) have no effect on systemic calcium levels we performed additional testing in rats and found that 20(OH)D3 had no calcemic activity at concentration as high as 1 µg/kg, whereas, 1,20(OH)2D3 was slightly to moderately calcemic and 1,25(OH)2D3 had strong calcemic activity.ConclusionsWe identified novel secosteroids that are excellent candidates for anti-leukemia therapy with 20(OH)D3 deserving special attention because of its relatively high potency and lack of calcemic activity.

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“…ChIP assays were conducted as described previously [38], [39]. In brief, approximately 2×10 9 cells in 150 mm dishes were first treated with PBS containing 1% formaldehyde for 10 min, washed twice with cold PBS, and incubated with 100 mM Tris-HCl (pH 9.4)/10 mM DTT at 30° for 20 min.…”

Section: Methodsmentioning

confidence: 99%

Repressive Effects of Resveratrol on Androgen Receptor Transcriptional Activity

et al. 2009

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BackgroundThe chemopreventive effects of resveratrol (RSV) on prostate cancer have been well established; the androgen receptor (AR) plays pivotal roles in prostatic tumorigenesis. However, the exact underlying molecular mechanisms about the effects of RSV on AR have not been fully elucidated. A model system is needed to determine whether and how RSV represses AR transcriptional activity.MethodologyThe AR cDNA was first cloned into the retroviral vector pOZ-N and then integrated into the genome of AR-negative HeLa cells to generate the AR(+) cells. The constitutively expressed AR was characterized by monitoring hormone-stimulated nuclear translocation, DNA binding, and transcriptional activation, with the AR(-) cells serving as controls. AR(+) cells were treated with RSV, and both AR protein levels and AR transcriptional activity were measured simultaneously. Chromatin immunoprecipitation (ChIP) assays were used to detect the effects of RSV on the recruitment of AR to its cognate element (ARE).ResultsAR in the AR (+) stable cell line functions in a manner similar to that of endogenously expressed AR. Using this model system we clearly demonstrated that RSV represses AR transcriptional activity independently of any effects on AR protein levels. However, neither the hormone-mediated nucleus translocation nor the AR/ARE interaction was affected by RSV treatment.ConclusionWe demonstrated unambiguously that RSV regulates AR target gene expression, at least in part, by repressing AR transcriptional activity. Repressive effects of RSV on AR activity result from mechanisms other than the affects of AR nuclear translocation or DNA binding.

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A critical role for the co-repressor N-CoR in erythroid differentiation and heme synthesis

Cited by 27 publications

References 48 publications

Clostridium perfringens α-toxin impairs erythropoiesis by inhibition of erythroid differentiation

Clostridium perfringens α-toxin impairs erythropoiesis by inhibition of erythroid differentiation

Products of Vitamin D3 or 7-Dehydrocholesterol Metabolism by Cytochrome P450scc Show Anti-Leukemia Effects, Having Low or Absent Calcemic Activity

Repressive Effects of Resveratrol on Androgen Receptor Transcriptional Activity

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