生长阻滞和DNA损伤诱生蛋白45(growth arrest and DNA damage inducible protein 45,Gadd45)基因家族属p53、BRCA1的下游基因,拥有Gadd45α、Gadd45β和Gadd45γ3个成员,其中Gadd45α可由多种损伤因素快速诱导产生,受p53和BRCA1的调节,...生长阻滞和DNA损伤诱生蛋白45(growth arrest and DNA damage inducible protein 45,Gadd45)基因家族属p53、BRCA1的下游基因,拥有Gadd45α、Gadd45β和Gadd45γ3个成员,其中Gadd45α可由多种损伤因素快速诱导产生,受p53和BRCA1的调节,在调控G2/M细胞周期监测点与维持基因组稳定性中起重要作用,从而抑制细胞转化和肿瘤的恶性进展。Gadd45β主要通过调控p53和JNK来抑制细胞生长及细胞凋亡的过程。Gadd45γ在基因损伤因子,如电离辐射、紫外线等诱导下而表达上调,受p53基因的调控,通过与MEKK4相互作用,在JNK和P38相关的凋亡途径中起作用,即通过细胞周期阻滞和细胞凋亡对细胞生长发挥负向调控,具有抑制细胞增殖和促进凋亡的作用。Gadd45基因不仅与细胞生存和凋亡有关,还参与细胞转化和肿瘤形成,但在不同的细胞状态下发挥不同甚至相反的作用。展开更多
Proteasome inhibitors have shown remarkable success in the treatment of hematologic neoplasm.There has been a lot of attention to applying these drugs for solid tumor treatment.Recent preclinical study has signified t...Proteasome inhibitors have shown remarkable success in the treatment of hematologic neoplasm.There has been a lot of attention to applying these drugs for solid tumor treatment.Recent preclinical study has signified the effectiveness on cell proliferation inhibition in lung adenocarcinoma treated by carfilzomib(CFZ),a second generation proteasome inhibitor.However,no insight has been gained regarding the mechanism.In this study,we have systematically investigated the CFZ functions in cell proliferation and growth,cell cycle arrest,and apoptosis in lung adenocarcinoma cells.Flow cytometry experiments showed that CFZ significantly induced G2/M cell cycle arrest and apoptosis in lung adenocarcinoma.MTS and colony formation assays revealed that CFZ substantially inhibited survival of lung adenocarcinoma cells.All results were consistently correlated to the upregulation expression of Gadd45a,which is an important gene in modulating cell cycle arrest and apoptosis in response to physiologic and environmental stresses.Here,upregulation of Gadd45a expression was observed after CFZ treatment.Knocking down Gadd45a expression suppressed G2/M arrest and apoptosis in CFZ-treated cells,and reduced cytotoxicity of this drug.The protein expression analysis has further identified that the AKT/FOXO3a pathway is involved in Gadd45a upregulation after CFZ treatment.These findings unveil a novel mechanism of proteasome inhibitor in anti-solid tumor activity,and shed light on novel preferable therapeutic strategy for lung adenocarcinoma.We believe that Gadd45a expression can be a highly promising candidate predictor in evaluating the efficacy of proteasome inhibitors in solid tumor therapy.展开更多
Ataxia telangiectasia mutated （ATM） kinase plays an essential role in the maintenance of genomic stability. ATM-deficient （ATM-/-） mice exhibit hematopoietic stem cell （HSC） dysfunction and a high incidence of l...Ataxia telangiectasia mutated （ATM） kinase plays an essential role in the maintenance of genomic stability. ATM-deficient （ATM-/-） mice exhibit hematopoietic stem cell （HSC） dysfunction and a high incidence of lym- phoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM-/- HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM-/- mice. Instead, ATM and Gadd45a double knockout （ATM-/- Gadd45a-/-） HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM-/- HSCs in HSC transplantation experiments. Fur- ther experiments revealed that the aggravated defect of ATM-/- Gadd45a-/- HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53-p21 signal- ing pathway. Additionally, ATM-/- Gadd45a-/- mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM-/- mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which sub- sequently resulted in a further impaired self-renewal capacity and an increased malignant transformation in ATM-/- HSCs.展开更多
遗传毒性评价是药物安全性评价的重要组成部分。如何早期、快速地获得药物可能的毒性反应数据,是当前遗传毒理学领域的研究热点之一。介绍几种目前应用比较广泛或有较好应用前景的早期、快速的遗传毒性评价方法,包括AmesII试验、Gadd45 ...遗传毒性评价是药物安全性评价的重要组成部分。如何早期、快速地获得药物可能的毒性反应数据,是当前遗传毒理学领域的研究热点之一。介绍几种目前应用比较广泛或有较好应用前景的早期、快速的遗传毒性评价方法,包括AmesII试验、Gadd45 Green Screen试验、高通量体外彗星试验和流式细胞术检测微核试验,主要围绕这些方法的基本原理、简要操作流程、预测毒性的可信度以及与传统方法相比的优缺点等展开。同时简要介绍计算机辅助毒性预测模型以及基因芯片技术在遗传毒性评价中的应用。展开更多
Bavachin is a dihydroflavonoid compound isolated from Psoralea corylifolia,and exhibits anti-bacterial,anti-inflammatory,anti-tumor and lipid-lowering activities.Recent attention has gradually drawn on bavachin-induce...Bavachin is a dihydroflavonoid compound isolated from Psoralea corylifolia,and exhibits anti-bacterial,anti-inflammatory,anti-tumor and lipid-lowering activities.Recent attention has gradually drawn on bavachin-induced apoptosis in many human cancer cell lines.However,the anti-cancer effects and related mechanisms in colorectal cancer remain unknown.Here,we investigated the effects of bavachin on colorectal cancer in vivo and in vitro.The results showed that bavachin inhibited the proliferation of human colorectal cancer cells and induce apoptosis.These changes were mediated by activating the MAPK signaling pathway,which significantly up-regulated the expression of Gadd45a.Furthermore,Gadd45a silencing obviously attenuated bavachin-mediated cell apoptosis.Inhibition of the MAPK signaling pathway by JNK/ERK/p38 inhibitors also weakened the up-regulation of Gadd45a by bavachin.The anticancer effect of bavachin was also validated using a mouse xenograft model of human colorectal cancer.In conclusion,these findings suggest that bavachin induces the apoptosis of colorectal cancer cells through activating the MAPK signaling pathway.展开更多
文摘生长阻滞和DNA损伤诱生蛋白45(growth arrest and DNA damage inducible protein 45,Gadd45)基因家族属p53、BRCA1的下游基因,拥有Gadd45α、Gadd45β和Gadd45γ3个成员,其中Gadd45α可由多种损伤因素快速诱导产生,受p53和BRCA1的调节,在调控G2/M细胞周期监测点与维持基因组稳定性中起重要作用,从而抑制细胞转化和肿瘤的恶性进展。Gadd45β主要通过调控p53和JNK来抑制细胞生长及细胞凋亡的过程。Gadd45γ在基因损伤因子,如电离辐射、紫外线等诱导下而表达上调,受p53基因的调控,通过与MEKK4相互作用,在JNK和P38相关的凋亡途径中起作用,即通过细胞周期阻滞和细胞凋亡对细胞生长发挥负向调控,具有抑制细胞增殖和促进凋亡的作用。Gadd45基因不仅与细胞生存和凋亡有关,还参与细胞转化和肿瘤形成,但在不同的细胞状态下发挥不同甚至相反的作用。
基金Project supported by the National Natural Science Foundation of China(Nos.81601992,81802986,and 81601029)the Natural Science Foundation of Zhejiang Province(No.LQ16H160008)the Medical and Health Program of Zhejiang Province(No.2019338991),China
文摘Proteasome inhibitors have shown remarkable success in the treatment of hematologic neoplasm.There has been a lot of attention to applying these drugs for solid tumor treatment.Recent preclinical study has signified the effectiveness on cell proliferation inhibition in lung adenocarcinoma treated by carfilzomib(CFZ),a second generation proteasome inhibitor.However,no insight has been gained regarding the mechanism.In this study,we have systematically investigated the CFZ functions in cell proliferation and growth,cell cycle arrest,and apoptosis in lung adenocarcinoma cells.Flow cytometry experiments showed that CFZ significantly induced G2/M cell cycle arrest and apoptosis in lung adenocarcinoma.MTS and colony formation assays revealed that CFZ substantially inhibited survival of lung adenocarcinoma cells.All results were consistently correlated to the upregulation expression of Gadd45a,which is an important gene in modulating cell cycle arrest and apoptosis in response to physiologic and environmental stresses.Here,upregulation of Gadd45a expression was observed after CFZ treatment.Knocking down Gadd45a expression suppressed G2/M arrest and apoptosis in CFZ-treated cells,and reduced cytotoxicity of this drug.The protein expression analysis has further identified that the AKT/FOXO3a pathway is involved in Gadd45a upregulation after CFZ treatment.These findings unveil a novel mechanism of proteasome inhibitor in anti-solid tumor activity,and shed light on novel preferable therapeutic strategy for lung adenocarcinoma.We believe that Gadd45a expression can be a highly promising candidate predictor in evaluating the efficacy of proteasome inhibitors in solid tumor therapy.
文摘Ataxia telangiectasia mutated （ATM） kinase plays an essential role in the maintenance of genomic stability. ATM-deficient （ATM-/-） mice exhibit hematopoietic stem cell （HSC） dysfunction and a high incidence of lym- phoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM-/- HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM-/- mice. Instead, ATM and Gadd45a double knockout （ATM-/- Gadd45a-/-） HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM-/- HSCs in HSC transplantation experiments. Fur- ther experiments revealed that the aggravated defect of ATM-/- Gadd45a-/- HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53-p21 signal- ing pathway. Additionally, ATM-/- Gadd45a-/- mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM-/- mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which sub- sequently resulted in a further impaired self-renewal capacity and an increased malignant transformation in ATM-/- HSCs.
文摘遗传毒性评价是药物安全性评价的重要组成部分。如何早期、快速地获得药物可能的毒性反应数据,是当前遗传毒理学领域的研究热点之一。介绍几种目前应用比较广泛或有较好应用前景的早期、快速的遗传毒性评价方法,包括AmesII试验、Gadd45 Green Screen试验、高通量体外彗星试验和流式细胞术检测微核试验,主要围绕这些方法的基本原理、简要操作流程、预测毒性的可信度以及与传统方法相比的优缺点等展开。同时简要介绍计算机辅助毒性预测模型以及基因芯片技术在遗传毒性评价中的应用。
基金This work was supported by the National Natural Science Foundation of China(No.81472233)the“Double First-Class”University Project(No.CPU2018GF/GY16)+1 种基金the“111 Project”from the Ministry of Education of Chinathe Project Funded by the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions.
文摘Bavachin is a dihydroflavonoid compound isolated from Psoralea corylifolia,and exhibits anti-bacterial,anti-inflammatory,anti-tumor and lipid-lowering activities.Recent attention has gradually drawn on bavachin-induced apoptosis in many human cancer cell lines.However,the anti-cancer effects and related mechanisms in colorectal cancer remain unknown.Here,we investigated the effects of bavachin on colorectal cancer in vivo and in vitro.The results showed that bavachin inhibited the proliferation of human colorectal cancer cells and induce apoptosis.These changes were mediated by activating the MAPK signaling pathway,which significantly up-regulated the expression of Gadd45a.Furthermore,Gadd45a silencing obviously attenuated bavachin-mediated cell apoptosis.Inhibition of the MAPK signaling pathway by JNK/ERK/p38 inhibitors also weakened the up-regulation of Gadd45a by bavachin.The anticancer effect of bavachin was also validated using a mouse xenograft model of human colorectal cancer.In conclusion,these findings suggest that bavachin induces the apoptosis of colorectal cancer cells through activating the MAPK signaling pathway.
