Nanog is a newly identified homeodomain gene that functions to sustain the pluripotency of embryonic stem cells.However,the molecular mechanism through which nanog regulates stem cell pluripotency remains unknown.Mous...Nanog is a newly identified homeodomain gene that functions to sustain the pluripotency of embryonic stem cells.However,the molecular mechanism through which nanog regulates stem cell pluripotency remains unknown.Mouse nanog encodes a polypeptide of 305 residues with a divergent homeodomain similar to those in the NK-2 family.The rest ofnanog contains no apparent homology to any known proteins characterized so far.It is hypothesized that nanog encodes a transcription factor that regulates stem cell pluripotency by switching on or off target genes.To test this hypothesis,we constructed fusion proteins between nanog and DNA binding domains of the yeast transcription factor Gal4 and tested the transactivation potentials of these constructs.Our data demonstrate that both regions N- and C- terminal to the homeodomain have transcription activities.Despite the fact that it contains no apparent transactivation motifs,the C-terminal domain is about 7 times as active as the N-terminal one.This unique arrangement of dual transactivators may confer nanog the flexibility and specificity to regulate downstream genes critical for both pluripotency and differentiation of stem cells.展开更多
Tumor necrosis factor α （TNF-α） has been recognized as an activator of nuclear factor kB （NF-kB）, a factor implicated in the protection of many cell types from apoptosis. We and others have presented evidence to...Tumor necrosis factor α （TNF-α） has been recognized as an activator of nuclear factor kB （NF-kB）, a factor implicated in the protection of many cell types from apoptosis. We and others have presented evidence to suggest that Fas-induced apoptosis may be an important aspect of the resolution of inflammation, and that delayed resolution of inflammation may be directly associated with NF-kB-dependent resistance to Fas. Because TNF-α activates NF-kB in many cell types including inflammatory cells such as eosinophils, we examined effects of TNF-α signaling on the Fas-mediated killing of an eosinophilic cell line AML14. While agonist anti-Fas （CHII） treatment induced apoptosis in AML14 cells, no significant cell death occurred in response to TNF-α alone. Electrophoretic mobility shift assay （EMSA） revealed that TNF-α induced NF-kB transactivation in AMLI4 cells in a time- and dose-dependent fashion, and subsequent supershift assays indicated that the translocated NF-kB was the heterodimer p65 （RelA）/p50. Pre-treatment of cells with TNF-α dramatically decreased the CHll-induced cell death in a transient fashion, accompanied by suppression of activation of caspase-8 and caspase-3 activation. Inhibition of NF-kB transactivation by inhibitors, BAY 11-7085 and parthenolide, reversed the suppression of Fas-mediated apoptosis by TNF-α. Furthermore, TNF-α up-regulated X-linked inhibitor of apoptosis protein （XIAP） transiently and XIAP levels were correlated with the temporal pattern of TNF-α protection against Fas-mediated apoptosis. This finding suggested that TNF-α may contribute to the prolonged survival of inflammatory cells by suppression of Fas-mediated apoptosis, the process involved with NF-kB transactivation, anti-apoptotic XIAP up-regulation and caspase suppression. Cellular ＆ Molecular Immunology. 2007;4（1）：43-52.展开更多
Vitamin D3(VD3)is a multifunctional nutrient which can be either synthesized or absorbed from the diet.It plays a pivotal role in systemic calcium and phosphate homeostasis,as well as in various physiological and path...Vitamin D3(VD3)is a multifunctional nutrient which can be either synthesized or absorbed from the diet.It plays a pivotal role in systemic calcium and phosphate homeostasis,as well as in various physiological and pathological processes.VD3 is converted to the active form,1α,25-dihydroxy vitamin D3(1,25-D3),by cytochrome P4502R1(CYP2R1)/CYP27A1 and CYP27B1 sequentially,and deactivated by multiple enzymes including CYP3A4.On the other hand,1,25-D3 is capable of activating the transcription of CYP3A genes in humans,mice and rats.The vitamin D receptor(VDR)-mediated transactivation of human CYP3A4 and CYP3A5 resembles that known for pregnane X receptor(PXR).Activated VDR forms a heterodimer with retinoid X receptorα(RXRα),recruits co-activators,translocates to the cell nucleus,binds to the specific vitamin D responsive elements(VDRE),and activates the gene transcription.In mice,intestinal Cyp3a11 mRNA levels,but not those of hepatic CYP3As,were induced by in vivo administration of VDR and PXR agonists.In rats,intestinal Cyp3a1 and Cyp3a2mRNAs were induced by 1,25-D3 or lithocholic acid(LCA),whereas hepatic Cyp3a2,but not Cyp3a1and Cyp3a9,was modulated to 1,25-D3 treatment.In general,the VDR-mediated regulation of CYP3A presents species and organ specificity.展开更多
基金supported in part by the Tsinghua University BaiRen Scholar Program,NSFC 30270287the 973 Project--2001CB5101 from The Ministry of Science and Technology of China.
文摘Nanog is a newly identified homeodomain gene that functions to sustain the pluripotency of embryonic stem cells.However,the molecular mechanism through which nanog regulates stem cell pluripotency remains unknown.Mouse nanog encodes a polypeptide of 305 residues with a divergent homeodomain similar to those in the NK-2 family.The rest ofnanog contains no apparent homology to any known proteins characterized so far.It is hypothesized that nanog encodes a transcription factor that regulates stem cell pluripotency by switching on or off target genes.To test this hypothesis,we constructed fusion proteins between nanog and DNA binding domains of the yeast transcription factor Gal4 and tested the transactivation potentials of these constructs.Our data demonstrate that both regions N- and C- terminal to the homeodomain have transcription activities.Despite the fact that it contains no apparent transactivation motifs,the C-terminal domain is about 7 times as active as the N-terminal one.This unique arrangement of dual transactivators may confer nanog the flexibility and specificity to regulate downstream genes critical for both pluripotency and differentiation of stem cells.
文摘Tumor necrosis factor α （TNF-α） has been recognized as an activator of nuclear factor kB （NF-kB）, a factor implicated in the protection of many cell types from apoptosis. We and others have presented evidence to suggest that Fas-induced apoptosis may be an important aspect of the resolution of inflammation, and that delayed resolution of inflammation may be directly associated with NF-kB-dependent resistance to Fas. Because TNF-α activates NF-kB in many cell types including inflammatory cells such as eosinophils, we examined effects of TNF-α signaling on the Fas-mediated killing of an eosinophilic cell line AML14. While agonist anti-Fas （CHII） treatment induced apoptosis in AML14 cells, no significant cell death occurred in response to TNF-α alone. Electrophoretic mobility shift assay （EMSA） revealed that TNF-α induced NF-kB transactivation in AMLI4 cells in a time- and dose-dependent fashion, and subsequent supershift assays indicated that the translocated NF-kB was the heterodimer p65 （RelA）/p50. Pre-treatment of cells with TNF-α dramatically decreased the CHll-induced cell death in a transient fashion, accompanied by suppression of activation of caspase-8 and caspase-3 activation. Inhibition of NF-kB transactivation by inhibitors, BAY 11-7085 and parthenolide, reversed the suppression of Fas-mediated apoptosis by TNF-α. Furthermore, TNF-α up-regulated X-linked inhibitor of apoptosis protein （XIAP） transiently and XIAP levels were correlated with the temporal pattern of TNF-α protection against Fas-mediated apoptosis. This finding suggested that TNF-α may contribute to the prolonged survival of inflammatory cells by suppression of Fas-mediated apoptosis, the process involved with NF-kB transactivation, anti-apoptotic XIAP up-regulation and caspase suppression. Cellular ＆ Molecular Immunology. 2007;4（1）：43-52.
基金supported in part by grants from the National Natural Science Foundation of China(No.81773808)the Science and Technology Commission of Shanghai Municipality(Nos.17140901000,17140901001 and 18430760400,China).
文摘Vitamin D3(VD3)is a multifunctional nutrient which can be either synthesized or absorbed from the diet.It plays a pivotal role in systemic calcium and phosphate homeostasis,as well as in various physiological and pathological processes.VD3 is converted to the active form,1α,25-dihydroxy vitamin D3(1,25-D3),by cytochrome P4502R1(CYP2R1)/CYP27A1 and CYP27B1 sequentially,and deactivated by multiple enzymes including CYP3A4.On the other hand,1,25-D3 is capable of activating the transcription of CYP3A genes in humans,mice and rats.The vitamin D receptor(VDR)-mediated transactivation of human CYP3A4 and CYP3A5 resembles that known for pregnane X receptor(PXR).Activated VDR forms a heterodimer with retinoid X receptorα(RXRα),recruits co-activators,translocates to the cell nucleus,binds to the specific vitamin D responsive elements(VDRE),and activates the gene transcription.In mice,intestinal Cyp3a11 mRNA levels,but not those of hepatic CYP3As,were induced by in vivo administration of VDR and PXR agonists.In rats,intestinal Cyp3a1 and Cyp3a2mRNAs were induced by 1,25-D3 or lithocholic acid(LCA),whereas hepatic Cyp3a2,but not Cyp3a1and Cyp3a9,was modulated to 1,25-D3 treatment.In general,the VDR-mediated regulation of CYP3A presents species and organ specificity.
