Squamous cell carcinoma (SCC) is a significant cause of cancer morbidity and mortality worldwide, with an incidence of up to 166 cases per 100 000 population. It arises in the skin, upper aerodigestive tract, lung, an...Squamous cell carcinoma (SCC) is a significant cause of cancer morbidity and mortality worldwide, with an incidence of up to 166 cases per 100 000 population. It arises in the skin, upper aerodigestive tract, lung, and cervix and affects more than 200 000 Americans each year. We report here that a microarray experiment comparing 41 SCC and 13 normal tissue specimens showed that Id2, a gene that controls the cell cycle, was significantly up-regulated in SCC. Enforced expression of Id2 in vitro stimulated the proliferation of SCC cells and up-regulated the transcription of nuclear factor kappa B (NF-κB) and cyclin D1. Enhancement of the NF-κB activity with p65 significantly increased the cell proliferation and the transcription of cyclin D1, whereas inhibition of the NF-κB activity with I kappa B alpha mutant (IκBα M) and pyrroline dithiocarbamate (PDTC) abrogated cell proliferation and transcription of cyclin D1. Furthermore, a mutated NF-κB binding site in the cyclin D1 promoter fully abrogated the Id2-induced transcription of cyclin D1. Taken together, these data indicate that Id2 induces SCC tumor growth and proliferation through the NF-κB/cyclin D1 pathway.展开更多
目的研究DNA结合抑制物2(inhibitor of DNA binding2,Id2)在室管膜前下区(anteriorsubventricularzone,SVZa)神经干细胞向神经元分化中的作用。方法体外分离培养P0昆明小鼠SVZa神经干细胞,正义Id2、反义Id2真核表达质粒转染SVZa神经干细...目的研究DNA结合抑制物2(inhibitor of DNA binding2,Id2)在室管膜前下区(anteriorsubventricularzone,SVZa)神经干细胞向神经元分化中的作用。方法体外分离培养P0昆明小鼠SVZa神经干细胞,正义Id2、反义Id2真核表达质粒转染SVZa神经干细胞,采用流式细胞仪检测在Id2作用下SVZa神经干细胞分化为神经元的比例。采用Western blot检测不同浓度的骨形成蛋白2(bonemorphogenenticprotein2,BMP2)诱导下Id2蛋白的表达变化。结果正义Id2真核表达质粒转染组,SVZa神经干细胞分化为神经元的比例小于空白对照组,反义Id2真核表达质粒转染组,SVZa神经干细胞分化为神经元的比例明显高于空白对照组;随着BMP2浓度的增加,Id2的表达增加。结论Id2抑制体外培养的P0SVZa神经干细胞向神经元方向分化,BMP2可以促进SVZa神经干细胞Id2的表达,它们共同参与调控SVZa神经干细胞向神经元分化的过程。展开更多
CD8^(+)T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(Tex^(prog))and Tim-^(3+)terminally exhausted(Tex^(term))subpopulatio...CD8^(+)T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(Tex^(prog))and Tim-^(3+)terminally exhausted(Tex^(term))subpopulations.Inhibitor of DNA binding protein 2(Id2)has been shown to play important roles in T-cell development and CD8^(+)T-cell immunity.However,the role of Id2 in CD8^(+)T-cell exhaustion is unclear.Here,we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm cells.Genetic deletion of Id2 dampens CD8^(+)T-cell-mediated immune responses and the maintenance of stem-like CD8^(+)T-cell subpopulations,suppresses PD-1 blockade and increases tumor susceptibility.Mechanistically,through its HLH domain,Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex,and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase LSD1.Therefore,Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter,modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+Texprog cells.An LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing mice.Inhibition of LSD1 increases the abundance of Slamf6^(+)Tim-3^(−)Tex^(prog) cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+T cells.This study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8^(+)T-cell exhaustion,and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.展开更多
目的研究DNA结合抑制物2(inhibitor of DNA binding2,Id2)在ApcΔ716/+小鼠家族性腺瘤性息肉病(familial adenomatous polyposis,FAP)发生中的作用。方法 Id2基因缺失的基因工程小鼠和家族性腺瘤性息肉病模型ApcΔ716/+小鼠杂交后,统计...目的研究DNA结合抑制物2(inhibitor of DNA binding2,Id2)在ApcΔ716/+小鼠家族性腺瘤性息肉病(familial adenomatous polyposis,FAP)发生中的作用。方法 Id2基因缺失的基因工程小鼠和家族性腺瘤性息肉病模型ApcΔ716/+小鼠杂交后,统计ApcΔ716/+小鼠与ApcΔ716/+Id2-/-杂交小鼠小肠肠道息肉的数目及总负荷,通过Western blot及原位杂交技术测定腺瘤性息肉Id2的表达。结果腺瘤性息肉组织中Id2蛋白及mRNA表达明显升高,相比ApcΔ716/+Id2野生型小鼠,ApcΔ716/+Id2-/-杂交小鼠肠道息肉总数目与不同大小的肠道息肉数目有明显减少(P均<0.05)。结论肠道腺瘤性息肉组织中Id2表达升高,Id2的缺失能抑制ApcΔ716/+小鼠肠道腺瘤性息肉的发生,Id2在人类家族性腺瘤性息肉病中可能发挥着促进肠道息肉形成的作用。展开更多
Objective： Id2 is a natural inhibitor of the basic helix-loop-helix（bHLH） transcription factors. Although it is well known that active ld2 prevents differentiation and promotes cell cycle progression and tumorigene...Objective： Id2 is a natural inhibitor of the basic helix-loop-helix（bHLH） transcription factors. Although it is well known that active ld2 prevents differentiation and promotes cell cycle progression and tumorigenesis, the molecular events that regulate Id2 activity remain to be investigated. Methods： Yeast two-hybrid, mammalian two-hybrid, GST-pulldown and immunoprecipitation （ColP） assays were used to screen and identify novel Id2 interactors. Luciferase assays were used to detect E47-mediated transcription activity. Colony formation and BrdU incorporation assays were used to determine cellular proliferation abilities. Northorn blot, western blot and quantitative PCR methods were used to measure gene expression levels. Electrophoretic mobility shift assays （EMSAs） were performed to investigate protein/DNA binding. Results： The LIM-only protein FHL2 （four-and-a-half-LIM-only protein 2） was identified to be a novel Id2 interactor. The HLH domain within Id2 is not required for its interaction with FHL2. FHL2 antagonizes the inhibitory effect of Id2 on the basic helix-loop-helix protein E47-mediated transcription. FHL2 prevents the formation of Id2-E47 heterdimer, thus releasing E47 to its target DNA and restoring its transcriptional activity. FHL2 expression was remarkably up-regulated during retinoic acid-induced differentiation of neuroblastoma cells, during which the expression of Id2 is opposite to that. Ectopic FHL2 expression in neuroblastoma cells markedly reduces the transcriptional and cell-cycle promoting functions of Id2. Conclusion： These results indicate that FHL2 is an important repressor of the oncogenic activity of Id2 in neuroblastoma cells.展开更多
Research on innate lymphoid cells （ILC） has recently been a fast paced topic of immunological research. As ILCs are able to produce signature Th cytokine, ILCs have garnered considerable attention and have been desc...Research on innate lymphoid cells （ILC） has recently been a fast paced topic of immunological research. As ILCs are able to produce signature Th cytokine, ILCs have garnered considerable attention and have been described to represent the innate counterpart of the CD4＋ T helper （Th） cells. The development and function of ILCs are precisely regulated by a network of crucial tran- scription factors, which are also involved in the devel- opment or differentiation of conventional natural killer （cNK） cells and T cells. In this review, we will summarize the key transcriptional regulators and their functions through each phases of ILC development. With the phase of ILC lineage commitment, we will focus in particular on the roles of the transcription regulators Id2 and GATA-3, which in collaboration with other transcriptional factors, are critically involved in the generation of ILC fate determined progenitors. Once an ILC lineage has been established, several other transcription factors are required for the specification and functional regulation of distinct mature ILC subsets. Thus, a comprehensive understanding of the interactions and regulatory mech- anisms mediated by these transcription factors will help us to further understand how ILCs exert their helper-like functions and bridge the innate and adaptive immunity.展开更多
文摘Squamous cell carcinoma (SCC) is a significant cause of cancer morbidity and mortality worldwide, with an incidence of up to 166 cases per 100 000 population. It arises in the skin, upper aerodigestive tract, lung, and cervix and affects more than 200 000 Americans each year. We report here that a microarray experiment comparing 41 SCC and 13 normal tissue specimens showed that Id2, a gene that controls the cell cycle, was significantly up-regulated in SCC. Enforced expression of Id2 in vitro stimulated the proliferation of SCC cells and up-regulated the transcription of nuclear factor kappa B (NF-κB) and cyclin D1. Enhancement of the NF-κB activity with p65 significantly increased the cell proliferation and the transcription of cyclin D1, whereas inhibition of the NF-κB activity with I kappa B alpha mutant (IκBα M) and pyrroline dithiocarbamate (PDTC) abrogated cell proliferation and transcription of cyclin D1. Furthermore, a mutated NF-κB binding site in the cyclin D1 promoter fully abrogated the Id2-induced transcription of cyclin D1. Taken together, these data indicate that Id2 induces SCC tumor growth and proliferation through the NF-κB/cyclin D1 pathway.
文摘目的研究DNA结合抑制物2(inhibitor of DNA binding2,Id2)在室管膜前下区(anteriorsubventricularzone,SVZa)神经干细胞向神经元分化中的作用。方法体外分离培养P0昆明小鼠SVZa神经干细胞,正义Id2、反义Id2真核表达质粒转染SVZa神经干细胞,采用流式细胞仪检测在Id2作用下SVZa神经干细胞分化为神经元的比例。采用Western blot检测不同浓度的骨形成蛋白2(bonemorphogenenticprotein2,BMP2)诱导下Id2蛋白的表达变化。结果正义Id2真核表达质粒转染组,SVZa神经干细胞分化为神经元的比例小于空白对照组,反义Id2真核表达质粒转染组,SVZa神经干细胞分化为神经元的比例明显高于空白对照组;随着BMP2浓度的增加,Id2的表达增加。结论Id2抑制体外培养的P0SVZa神经干细胞向神经元方向分化,BMP2可以促进SVZa神经干细胞Id2的表达,它们共同参与调控SVZa神经干细胞向神经元分化的过程。
基金supported by the Major Program of the National Natural Science Foundation of China(No.82293635,No.92169211)the National Key Research and Development Program of China(No.2019YFC1316302,No.2023YFC2306400)+1 种基金the National Natural Science Foundation of China(No.81972711)supported by the Science Fund Program for Distinguished Young Scholars(LC).
文摘CD8^(+)T-cell exhaustion is a state of dysfunction that promotes tumor progression and is marked by the generation of Slamf6^(+)progenitor exhausted(Tex^(prog))and Tim-^(3+)terminally exhausted(Tex^(term))subpopulations.Inhibitor of DNA binding protein 2(Id2)has been shown to play important roles in T-cell development and CD8^(+)T-cell immunity.However,the role of Id2 in CD8^(+)T-cell exhaustion is unclear.Here,we found that Id2 transcriptionally and epigenetically regulates the generation of Texprog cells and their conversion to Texterm cells.Genetic deletion of Id2 dampens CD8^(+)T-cell-mediated immune responses and the maintenance of stem-like CD8^(+)T-cell subpopulations,suppresses PD-1 blockade and increases tumor susceptibility.Mechanistically,through its HLH domain,Id2 binds and disrupts the assembly of the Tcf3-Tal1 transcriptional regulatory complex,and thus modulates chromatin accessibility at the Slamf6 promoter by preventing the interaction of Tcf3 with the histone lysine demethylase LSD1.Therefore,Id2 increases the abundance of the permissive H3K4me2 mark on the Tcf3-occupied E-boxes in the Slamf6 promoter,modulates chromatin accessibility at the Slamf6 promoter and epigenetically regulates the generation of Slamf6+Texprog cells.An LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing mice.Inhibition of LSD1 increases the abundance of Slamf6^(+)Tim-3^(−)Tex^(prog) cells in tumors and the expression level of Tcf1 in Id2-deleted CD8+T cells.This study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8^(+)T-cell exhaustion,and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.
文摘目的研究DNA结合抑制物2(inhibitor of DNA binding2,Id2)在ApcΔ716/+小鼠家族性腺瘤性息肉病(familial adenomatous polyposis,FAP)发生中的作用。方法 Id2基因缺失的基因工程小鼠和家族性腺瘤性息肉病模型ApcΔ716/+小鼠杂交后,统计ApcΔ716/+小鼠与ApcΔ716/+Id2-/-杂交小鼠小肠肠道息肉的数目及总负荷,通过Western blot及原位杂交技术测定腺瘤性息肉Id2的表达。结果腺瘤性息肉组织中Id2蛋白及mRNA表达明显升高,相比ApcΔ716/+Id2野生型小鼠,ApcΔ716/+Id2-/-杂交小鼠肠道息肉总数目与不同大小的肠道息肉数目有明显减少(P均<0.05)。结论肠道腺瘤性息肉组织中Id2表达升高,Id2的缺失能抑制ApcΔ716/+小鼠肠道腺瘤性息肉的发生,Id2在人类家族性腺瘤性息肉病中可能发挥着促进肠道息肉形成的作用。
基金supported by the National Natural Science Foundation of China (No.30870507)partially supported by a grant from the Ministry of Science and Technology of China (No.2005CB522603)
文摘Objective： Id2 is a natural inhibitor of the basic helix-loop-helix（bHLH） transcription factors. Although it is well known that active ld2 prevents differentiation and promotes cell cycle progression and tumorigenesis, the molecular events that regulate Id2 activity remain to be investigated. Methods： Yeast two-hybrid, mammalian two-hybrid, GST-pulldown and immunoprecipitation （ColP） assays were used to screen and identify novel Id2 interactors. Luciferase assays were used to detect E47-mediated transcription activity. Colony formation and BrdU incorporation assays were used to determine cellular proliferation abilities. Northorn blot, western blot and quantitative PCR methods were used to measure gene expression levels. Electrophoretic mobility shift assays （EMSAs） were performed to investigate protein/DNA binding. Results： The LIM-only protein FHL2 （four-and-a-half-LIM-only protein 2） was identified to be a novel Id2 interactor. The HLH domain within Id2 is not required for its interaction with FHL2. FHL2 antagonizes the inhibitory effect of Id2 on the basic helix-loop-helix protein E47-mediated transcription. FHL2 prevents the formation of Id2-E47 heterdimer, thus releasing E47 to its target DNA and restoring its transcriptional activity. FHL2 expression was remarkably up-regulated during retinoic acid-induced differentiation of neuroblastoma cells, during which the expression of Id2 is opposite to that. Ectopic FHL2 expression in neuroblastoma cells markedly reduces the transcriptional and cell-cycle promoting functions of Id2. Conclusion： These results indicate that FHL2 is an important repressor of the oncogenic activity of Id2 in neuroblastoma cells.
文摘Research on innate lymphoid cells （ILC） has recently been a fast paced topic of immunological research. As ILCs are able to produce signature Th cytokine, ILCs have garnered considerable attention and have been described to represent the innate counterpart of the CD4＋ T helper （Th） cells. The development and function of ILCs are precisely regulated by a network of crucial tran- scription factors, which are also involved in the devel- opment or differentiation of conventional natural killer （cNK） cells and T cells. In this review, we will summarize the key transcriptional regulators and their functions through each phases of ILC development. With the phase of ILC lineage commitment, we will focus in particular on the roles of the transcription regulators Id2 and GATA-3, which in collaboration with other transcriptional factors, are critically involved in the generation of ILC fate determined progenitors. Once an ILC lineage has been established, several other transcription factors are required for the specification and functional regulation of distinct mature ILC subsets. Thus, a comprehensive understanding of the interactions and regulatory mech- anisms mediated by these transcription factors will help us to further understand how ILCs exert their helper-like functions and bridge the innate and adaptive immunity.
