转录因子E2F1调节树突状细胞成熟的分子机制
摘要
近来的研究发现,转录因子E2F1除参与细胞周期调控,通过p53依赖和p53非依赖的两种方式参与细胞凋亡外,在造血系统细胞的发育分化上还起到重要调节作用。E2F1基因敲除鼠中淋巴细胞显著增生,但耐受下降并导致淋巴瘤。树突状细胞(DC)活化会诱导淋巴细胞增生,在E2F1基因敲除鼠中是否E2F1影响到DC的功能,从而引起淋巴细胞的异常?为此,本研究集中的研究了E2F1在树突状细胞中的调控作用和机制。
首先我们发现,在LPS诱导的人外周血单核细胞来源树突状细胞和鼠源树突状细胞系DC2.4成熟过程中,E2F1的基因转录和蛋白表达都表现出瞬时下降。利用所建立的DC2.4敲低或高表达E2F1细胞为模型分析和发现,敲低E2F1可导致DC2.4表型和功能都趋于成熟。相反,高表达E2F1能显著抑制LPS诱导的DC2.4的成熟。通过E2F1基因敲除鼠骨髓来源的DC表型的检测,验证了上述的研究结果,提示了E2F1对DC成熟起到反馈调节作用。
为了进一步揭示E2F1调控树突状细胞成熟的分子机制,利用所建立的DC2.4基因修饰细胞模型分析发现：敲低E2F1导致包括Erk1/2, NF-κB和PI3K/Akt等涉及树突状细胞成熟的主要信号通路活性明显增高。对E2F1可能参与的转录调节的部分基因分析发现,E2F1可影响信号通路中重要的接头蛋白Gab2的表达。对Gab2启动子的分析和实验研究发现,E2F1可能通过与Spl相互作用,从而对Gab2转录调节,并进一步影响了DC多个细胞信号通路的活性。
虽然Gab2参与多个细胞信号通路的活化,但Gab2的上调并未能完全模拟E2F1敲低所导致信号通路活性的所有变化,提示Gab2可能仅仅是众多E2F1下游调控基因中的一个,而E2F1诱导DC成熟可能是多个因子共同作用的综合结果。
本研究进一步扩展了转录因子E2F1的功能,首次阐明了其在DC成熟过程中的反馈调控作用及部分分子机制。研究结果显示,在DC成熟过程中E2F1的表达经历了先下调后恢复的动态变化过程,因此推测E2F1的反馈调节作用主要是在DC细胞成熟后期,避免DC过度活化,起到了很好的平衡机体内细胞稳态的作用。虽然已有研究报道在肿瘤细胞中E2F1对Gab2的表达调控,但本研究中发现在DC中E2F1对Gab2转录调控利用了不同的机制。本研究提示,Gab2可能在免疫细胞中发育和分化的新功能。
树突状细胞的成熟和活化在免疫应答中起到关键的作用,它功能的异常会直接关系到机体对病原体的抵抗和自身的保护。本研究成果为后续深入研究树突状细胞成熟的分子调控网络及对治疗用DC疫苗的研究打下了必要的基础。
Transcription factor E2F1has been largely studied as a promoter of S-phase transition in the cell cycle and cell apoptosis through p53-dependent or p53-independent pathways. Recent studies report that transcription factor E2F1regulates a set of genes during the development and differentiation of the hematopoietic cells. The E2F1gene knockout mice show more tumorigenesis such as lymphoma and lymphocytes hypoproliferations, but less tolerance. Dendritic cells (DCs) play the critical roles as professional APCs in the development of immune responses that induces protective immune responses or immune tolerance. However, it is unclear whether E2F1has any effect on DC phenotype or function.
We found that E2F1acts as a suppressor of DC maturation. The level of E2F1expression both in mRNA and protein were transiently downregulated in the course of LPS-induced maturation of both human monocyte-derived DCs and a mouse DC cell line, DC2.4. Knockdown of E2F1by small interfering RNA in DC2.4cells resulted in both phenotypic and functional maturation, even without LPS treatment. Conversely, ectopic overexpression of E2F1suppressed LPS-induced maturation of DC2.4cells. Moreover, the function of E2F1in regulating DC phenotypic maturation was confirmed with bone marrow-derived DCs from E2F1gene knockout mice.
To further investigat the mechnisms of feedback regulation of E2F1on DC maturation, the major cell signaling pathways involved in DC maturation were analysized in DC2.4cell with E2F1-knockdown. The results show that E2F1induced activation of multiple signaling pathways including PI3K, Erkl/2, NF-kappaB. Previously report has indicated that E2F1regulates Gab2, a transduction adaptor protein, in tumor cells. Indeed, examining of Gab2promoter revealed that E2F1regulates the expression of adaptor protein Gab2through transcriptional regulation of Gab2, and further influences multiple cell signaling. Though Gab2-knockdown shows effective on several major cell signaling pathways in DC2.4cell, however, depletion Gab2alone din not matches all the changes on signaling pathways that observed in E2F1-knockdown cells, indicating that Gab2may responsible for only partialy the effects of E2F1on altering the signaling pathways.
Overall, our study for the first time demonstrated that E2F1served as a negative feedback signal to prevent overreaction of DC maturation. The data further demonstrated that E2F1regulates Gab2may probably through inhibiting SP-1activity in the DCs that different from that was found in cancer cells.
首先我们发现,在LPS诱导的人外周血单核细胞来源树突状细胞和鼠源树突状细胞系DC2.4成熟过程中,E2F1的基因转录和蛋白表达都表现出瞬时下降。利用所建立的DC2.4敲低或高表达E2F1细胞为模型分析和发现,敲低E2F1可导致DC2.4表型和功能都趋于成熟。相反,高表达E2F1能显著抑制LPS诱导的DC2.4的成熟。通过E2F1基因敲除鼠骨髓来源的DC表型的检测,验证了上述的研究结果,提示了E2F1对DC成熟起到反馈调节作用。
为了进一步揭示E2F1调控树突状细胞成熟的分子机制,利用所建立的DC2.4基因修饰细胞模型分析发现：敲低E2F1导致包括Erk1/2, NF-κB和PI3K/Akt等涉及树突状细胞成熟的主要信号通路活性明显增高。对E2F1可能参与的转录调节的部分基因分析发现,E2F1可影响信号通路中重要的接头蛋白Gab2的表达。对Gab2启动子的分析和实验研究发现,E2F1可能通过与Spl相互作用,从而对Gab2转录调节,并进一步影响了DC多个细胞信号通路的活性。
虽然Gab2参与多个细胞信号通路的活化,但Gab2的上调并未能完全模拟E2F1敲低所导致信号通路活性的所有变化,提示Gab2可能仅仅是众多E2F1下游调控基因中的一个,而E2F1诱导DC成熟可能是多个因子共同作用的综合结果。
本研究进一步扩展了转录因子E2F1的功能,首次阐明了其在DC成熟过程中的反馈调控作用及部分分子机制。研究结果显示,在DC成熟过程中E2F1的表达经历了先下调后恢复的动态变化过程,因此推测E2F1的反馈调节作用主要是在DC细胞成熟后期,避免DC过度活化,起到了很好的平衡机体内细胞稳态的作用。虽然已有研究报道在肿瘤细胞中E2F1对Gab2的表达调控,但本研究中发现在DC中E2F1对Gab2转录调控利用了不同的机制。本研究提示,Gab2可能在免疫细胞中发育和分化的新功能。
树突状细胞的成熟和活化在免疫应答中起到关键的作用,它功能的异常会直接关系到机体对病原体的抵抗和自身的保护。本研究成果为后续深入研究树突状细胞成熟的分子调控网络及对治疗用DC疫苗的研究打下了必要的基础。
Transcription factor E2F1has been largely studied as a promoter of S-phase transition in the cell cycle and cell apoptosis through p53-dependent or p53-independent pathways. Recent studies report that transcription factor E2F1regulates a set of genes during the development and differentiation of the hematopoietic cells. The E2F1gene knockout mice show more tumorigenesis such as lymphoma and lymphocytes hypoproliferations, but less tolerance. Dendritic cells (DCs) play the critical roles as professional APCs in the development of immune responses that induces protective immune responses or immune tolerance. However, it is unclear whether E2F1has any effect on DC phenotype or function.
We found that E2F1acts as a suppressor of DC maturation. The level of E2F1expression both in mRNA and protein were transiently downregulated in the course of LPS-induced maturation of both human monocyte-derived DCs and a mouse DC cell line, DC2.4. Knockdown of E2F1by small interfering RNA in DC2.4cells resulted in both phenotypic and functional maturation, even without LPS treatment. Conversely, ectopic overexpression of E2F1suppressed LPS-induced maturation of DC2.4cells. Moreover, the function of E2F1in regulating DC phenotypic maturation was confirmed with bone marrow-derived DCs from E2F1gene knockout mice.
To further investigat the mechnisms of feedback regulation of E2F1on DC maturation, the major cell signaling pathways involved in DC maturation were analysized in DC2.4cell with E2F1-knockdown. The results show that E2F1induced activation of multiple signaling pathways including PI3K, Erkl/2, NF-kappaB. Previously report has indicated that E2F1regulates Gab2, a transduction adaptor protein, in tumor cells. Indeed, examining of Gab2promoter revealed that E2F1regulates the expression of adaptor protein Gab2through transcriptional regulation of Gab2, and further influences multiple cell signaling. Though Gab2-knockdown shows effective on several major cell signaling pathways in DC2.4cell, however, depletion Gab2alone din not matches all the changes on signaling pathways that observed in E2F1-knockdown cells, indicating that Gab2may responsible for only partialy the effects of E2F1on altering the signaling pathways.
Overall, our study for the first time demonstrated that E2F1served as a negative feedback signal to prevent overreaction of DC maturation. The data further demonstrated that E2F1regulates Gab2may probably through inhibiting SP-1activity in the DCs that different from that was found in cancer cells.
引文
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