目的:探讨cAMP反应元件结合蛋白5(cAMP response element-binding protein family 5,CREB5)对卵巢癌耐药细胞增殖及顺铂(DDP)敏感性的影响及机制。方法:免疫组织化学法观察DDP敏感和耐药卵巢癌组织中CREB5的表达情况。采用Western blot...目的:探讨cAMP反应元件结合蛋白5(cAMP response element-binding protein family 5,CREB5)对卵巢癌耐药细胞增殖及顺铂(DDP)敏感性的影响及机制。方法:免疫组织化学法观察DDP敏感和耐药卵巢癌组织中CREB5的表达情况。采用Western blot法比较DDP耐药卵巢癌细胞及其亲本细胞中CREB5的表达水平差异。敲减CREB5后,CCK-8法和EDU染色法评估DDP耐药卵巢癌细胞增殖活力,流式细胞术法检测顺铂诱导的细胞凋亡,Western blot法检测磷酸化细胞外信号调节激酶(phosphorylated extracellular signal regulated kinases,p-ERK)、血管内皮生长因子(vascular endothelial growth factor,VEGF)及劈开的半胱氨酸蛋白酶-3(Cleaved caspase-3)表达。肿瘤异体移植瘤模型检测敲减CREB5对耐药卵巢癌细胞体内生长和顺铂敏感性的影响。结果:CREB5在DDP耐药卵巢癌组织和DDP耐药卵巢癌细胞中的表达增高(P<0.05)。敲减CREB5后,DDP耐药卵巢癌细胞的增殖降低(P<0.05),顺铂诱导的细胞凋亡率增加(P<0.05),细胞中p-ERK和VEGF表达降低(P<0.05),Cleaved caspase-3表达增加(P<0.05)。敲减CREB5的DDP耐药细胞瘤在体内生长受阻且其对顺铂的敏感性增强,瘤体组织中p-ERK表达降低,Cleaved caspase-3表达增加。结论:敲减CREB5可抑制DDP耐药卵巢癌细胞增殖,并增强对顺铂敏感性,其机制可能与抑制p-ERK和VEGF表达并上调Cleaved caspase-3表达有关。展开更多
Virus-encoding RNA-dependent RNA polymerase(RdRp)is essential for genome replication and gene transcription of human coronaviruses(HCoVs),including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).We previo...Virus-encoding RNA-dependent RNA polymerase(RdRp)is essential for genome replication and gene transcription of human coronaviruses(HCoVs),including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).We previously identified the interaction between the catalytic subunit NSP12 of SARS-CoV-2 RdRp and the host protein CREB-regulated transcription coactivator 3(CRTC3),a member of the CRTC family that regulates cyclic AMP response element-binding protein(CREB)-mediated transcriptional activation.Currently,the implication of CRTC3 in the pathogenesis of HCoVs is poorly understood.Herein,we demonstrated that CRTC3 attenuates RdRp activity and SARS-CoV-2 genome replication,therefore reducing the production of progeny viruses.The interaction of CRTC3 with NSP12 contributes to its inhibitory effect on RdRp activity.Furthermore,we expanded the suppressive effects of two other CRTC family members(CRTC1 and CRTC2)on the RdRp activities of lethal HCoVs,including SARS-CoV-2 and Middle East respiratory syndrome coronavirus(MERS-CoV),along with the CREB antagonization.Overall,our research suggests that CRTCs restrict the replication of HCoVs and are antagonized by CREB,which not only provides new insights into the replication regulation of HCoVs,but also offers important information for the development of anti-HCoV interventions.展开更多
本研究旨在剖析环磷酸腺苷反应元件结合蛋白(CAMP Response Element Binding protein, CREB)相关的三种信号通路在疾病中的作用机制,以期为疾病治疗提供创新性的策略。我们采用综述的形式,通过计算机检索PubMed数据库、中国知网等权威资...本研究旨在剖析环磷酸腺苷反应元件结合蛋白(CAMP Response Element Binding protein, CREB)相关的三种信号通路在疾病中的作用机制,以期为疾病治疗提供创新性的策略。我们采用综述的形式,通过计算机检索PubMed数据库、中国知网等权威资源,筛选并整理与CREB信号通路相关的文献资料,进行了系统的分析和探讨。在ERK/CREB信号通路的研究中,我们发现该通路对长期记忆的形成具有破坏作用以及加速抑郁症的发展。在cAMP-PKA-CREB信号通路的研究中,我们发现这一通路对乳腺癌、肺癌等多种肿瘤疾病的进展具有重要影响。同时,在CaMKII/CREB/BDNF信号通路的研究中,我们发现该通路在疼痛的维持和产生过程中起到关键作用。综上所述,我们认为CREB及其信号通路在神经系统疾病、肿瘤疾病等多种疾病中发挥着至关重要的作用。The aim of this study is to analyze the mechanism of action of three signaling pathways related to CAMP Response Element Binding protein (CREB) in diseases, with a view to providing innovative strategies for disease treatment. In the form of a review, we searched authoritative resources such as PubMed database and CNKI by computer, screened and sorted out literature related to CREB signaling pathway, and carried out a systematic analysis and discussion. In our study of the ERK/CREB signaling pathway, we found that this pathway has a destructive effect on long-term memory formation and accelerates the development of depression. In the study of cAMP-PKA-CREB signaling pathway, we found that this pathway has an important impact on the progression of breast cancer, lung cancer and other tumor diseases. At the same time, in the study of CaMKII/CREB/BDNF signaling pathway, we found that this pathway plays a key role in the maintenance and production of pain. In summary, we believe that CREB and its signaling pathway play a crucial role in a variety of diseases, such as neurological diseases and tumor diseases.展开更多
抑郁症是一种以心境障碍为主要特征的精神类疾病,对人类的身心健康构成了重大的威胁。近年来,法尼醇X受体(farnesoid X receptor,FXR)已被发现在大脑海马体等脑区中表达,并与抑郁症的发病密切相关。其还可影响下游靶标环磷酸腺苷反应元...抑郁症是一种以心境障碍为主要特征的精神类疾病,对人类的身心健康构成了重大的威胁。近年来,法尼醇X受体(farnesoid X receptor,FXR)已被发现在大脑海马体等脑区中表达,并与抑郁症的发病密切相关。其还可影响下游靶标环磷酸腺苷反应元件结合蛋白(cAMP response element binding protein,CREB)-脑源性神经营养因子(brain-derived-neurotrophic factor,BDNF)信号通路,有望作为治疗抑郁症的新靶点。本文分析海马FXR如何调控CREB-BDNF信号通路,并总结与抑郁症发病机制相关的最新研究进展,以期为抑郁症的药物研发和临床治疗提供精准靶向的思路。展开更多
基金supported by grants from the National Natural Science Foundation of China(32071236)the National Science Fund for Distinguished Young Scholars(32225001)+6 种基金the 1.3.5 Project for Disciplines Excellence of West China Hospital,Sichuan University(ZYGD23018)Key Science and Technology Research Projects in Key Areas of the Corps(2023AB053)the National Key Research and Development Program of China(2022YFC2303700)the Joint Project of Pengzhou People's Hospital with Southwest Medical University(2024PZXNYD02)Project funded by China Postdoctoral Science Foundation(2020M683304)Sichuan Science and Technology Support Project(2021YJ0502)Post-Doctor Research Project,West China Hospital,Sichuan University(2020HXBH082).
文摘Virus-encoding RNA-dependent RNA polymerase(RdRp)is essential for genome replication and gene transcription of human coronaviruses(HCoVs),including severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).We previously identified the interaction between the catalytic subunit NSP12 of SARS-CoV-2 RdRp and the host protein CREB-regulated transcription coactivator 3(CRTC3),a member of the CRTC family that regulates cyclic AMP response element-binding protein(CREB)-mediated transcriptional activation.Currently,the implication of CRTC3 in the pathogenesis of HCoVs is poorly understood.Herein,we demonstrated that CRTC3 attenuates RdRp activity and SARS-CoV-2 genome replication,therefore reducing the production of progeny viruses.The interaction of CRTC3 with NSP12 contributes to its inhibitory effect on RdRp activity.Furthermore,we expanded the suppressive effects of two other CRTC family members(CRTC1 and CRTC2)on the RdRp activities of lethal HCoVs,including SARS-CoV-2 and Middle East respiratory syndrome coronavirus(MERS-CoV),along with the CREB antagonization.Overall,our research suggests that CRTCs restrict the replication of HCoVs and are antagonized by CREB,which not only provides new insights into the replication regulation of HCoVs,but also offers important information for the development of anti-HCoV interventions.
文摘本研究旨在剖析环磷酸腺苷反应元件结合蛋白(CAMP Response Element Binding protein, CREB)相关的三种信号通路在疾病中的作用机制,以期为疾病治疗提供创新性的策略。我们采用综述的形式,通过计算机检索PubMed数据库、中国知网等权威资源,筛选并整理与CREB信号通路相关的文献资料,进行了系统的分析和探讨。在ERK/CREB信号通路的研究中,我们发现该通路对长期记忆的形成具有破坏作用以及加速抑郁症的发展。在cAMP-PKA-CREB信号通路的研究中,我们发现这一通路对乳腺癌、肺癌等多种肿瘤疾病的进展具有重要影响。同时,在CaMKII/CREB/BDNF信号通路的研究中,我们发现该通路在疼痛的维持和产生过程中起到关键作用。综上所述,我们认为CREB及其信号通路在神经系统疾病、肿瘤疾病等多种疾病中发挥着至关重要的作用。The aim of this study is to analyze the mechanism of action of three signaling pathways related to CAMP Response Element Binding protein (CREB) in diseases, with a view to providing innovative strategies for disease treatment. In the form of a review, we searched authoritative resources such as PubMed database and CNKI by computer, screened and sorted out literature related to CREB signaling pathway, and carried out a systematic analysis and discussion. In our study of the ERK/CREB signaling pathway, we found that this pathway has a destructive effect on long-term memory formation and accelerates the development of depression. In the study of cAMP-PKA-CREB signaling pathway, we found that this pathway has an important impact on the progression of breast cancer, lung cancer and other tumor diseases. At the same time, in the study of CaMKII/CREB/BDNF signaling pathway, we found that this pathway plays a key role in the maintenance and production of pain. In summary, we believe that CREB and its signaling pathway play a crucial role in a variety of diseases, such as neurological diseases and tumor diseases.
文摘抑郁症是一种以心境障碍为主要特征的精神类疾病,对人类的身心健康构成了重大的威胁。近年来,法尼醇X受体(farnesoid X receptor,FXR)已被发现在大脑海马体等脑区中表达,并与抑郁症的发病密切相关。其还可影响下游靶标环磷酸腺苷反应元件结合蛋白(cAMP response element binding protein,CREB)-脑源性神经营养因子(brain-derived-neurotrophic factor,BDNF)信号通路,有望作为治疗抑郁症的新靶点。本文分析海马FXR如何调控CREB-BDNF信号通路,并总结与抑郁症发病机制相关的最新研究进展,以期为抑郁症的药物研发和临床治疗提供精准靶向的思路。
