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Mouse modelling of the MDM2/mdmx-p53 signalling axis

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Journal of Molecular Cell Biology 2017年第1期9卷 34-44页

作者： Nicole R. Tackmann Yanping Zhang Department of Radiation Oncology Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill Chapel Hill NC 27514 USA Curriculum in Genetics and MoLecular Biology School of Medicine University of North Carolina at Chapel HiLl Chapel HILL NC 27514 USA Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy Cancer Institute Xuzhou Medical College Xuzhou 221002 China

It is evident that p53 activity is critical for tumour prevention and stress response through its transcriptional activation of genes affecting cellular senescence, apoptosis, cellular metabolism, and DNA repair. The regulation of p53 is highly complex, and MDM2 and mdmx are thought to be critical for deciding the fate of p53, both through inhibitory binding and post-translational modification. Many mouse models have been generated to study the regulation of p53 in vivo, and they have altered our inter- pretations of how p53 is regulated by MDM2 and mdmx. Although MDM2 is absolutely required for p53 regulation, certain func- tions are dispensable under unstressed conditions, including the ability of MDM2 to degrade p53. mdmx, on the other hand, may only be required in select situations, like embryogenesis. These models have also clarified how cellular stress signals modify the p53-inhibiting activities of MDM2 and mdmx in vivo. It is clear that more work will need to be performed to further understand the contexts for each of these signals and the requirements of various MDM2 and mdmx functions. Here, we will discuss what we have learned from mouse modelling of MDM2 and mdmx and underscore the ways in which these models could inform future therapies.

关键词： p53 MDM2 mdmx E3 ubiquitin ligase cancer

Design of ultrahigh-affinity and dual-specificity peptide antagonists of MDM2 and mdmx for P53 activation and tumor suppression

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Acta Pharmaceutica Sinica B 2021年第9期11卷 2655-2669页

作者： Xiang Li Neelakshi Gohain Si Chen Yinghua Li Xiaoyuan Zhao Bo Li William D.Tolbert Wangxiao He Marzena Pazgier Honggang Hu Wuyuan Lu School of Pharmacy Second Military Medical UniversityShanghai 200433China Institute of Human Virology and Department of Biochemistry and Molecular Biology University of Maryland School of MedicineBaltimoreMD 21201USA School of Medicine Shanghai UniversityShanghai 200444China Institute of Translational Medicine Shanghai UniversityShanghai 200444China State Key Laboratory of Rare Earth Resource Utilization Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China Department of Talent Highland the First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an 710061China Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS)of School of Basic Medical Sciences and Shanghai Institute of Infectious Disease and Biosecurity of School of Public Health Fudan UniversityShanghai 200032China

Peptide inhibition of the interactions of the tumor suppressor protein P53 with its negative regulators MDM2 and mdmx activates P53 in vitro and in vivo,representing a viable therapeutic strategy for cancer *** phage display techniques,we previously identified a potent peptide activator of P53,termed PMI(TSFAEYWNLLSP),with binding affinities for both MDM2 and mdmx in the low nanomolar concentration *** we report an ultrahigh affinity,dual-specificity peptide antagonist of MDM2 and mdmx obtained through systematic mutational analysis and additivitybased molecular *** assays of over 100 peptide analogs of PMI using surface plasmon resonance and fluorescence polarization techniques yielded a dodecameric peptide termed PMI-M3(LTFLEYWAQLMQ)that bound to MDM2 and mdmx with K_(d)values in the low picomolar concentration range as verified by isothermal titration ***-crystal structures of MDM2 and of mdmx in complex with PMI-M3 were solved at 1.65 and 3.0 A resolution,*** to PMI,PMI-M3 occupied the P53-binding pocket of MDM2/mdmx,which was dominated energetically by intermolecular interactions involving Phe3,Tyr6,Trp7,and Leu *** differences in binding between PMI-M3 and PMI were observed at other positions such as Leu4 and Met11 with MDM2,and Leu1 and Met11 with mdmx,collectively contributing to a significantly enhanced binding affinity of PMI-M3 for both *** adding lysine residues to both ends of PMI and PMI-M3 to improve their cellular uptake,we obtained modified peptides termed PMI-2K(KTSFAEYWNLLSPK)and M3-2K(KLTFLEYWAQLMQK).Compared with PMI-2K,M3-2K exhibited significantly improved antitumor activities in vitro and in vivo in a P53-dependent *** super-strong peptide inhibitor of the P53-MDM2/mdmx interactions may become,in its own right,a powerful lead compound for anticancer drug development,and can aid molecular design of other classes of P53 activators as well for anticancer therapy.

关键词： MDM2 mdmx P53 Antitumor peptide Systematic mutational analysis

Role of Mdm2 and mdmx in DNA repair

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Journal of Molecular Cell Biology 2017年第1期9卷 69-73页

作者： Christine M. Eischen Department of Cancer Biology Sidney Kimmel Cancer Center Thomas Jefferson University Philadelphia PA 19107 USA

Mdm2 and mdmx are critical regulators of the p53 tumour suppressor and are overexpressed in many human malignancies. However, in recent years, their impact on genome instability was shown to be at least, in part, independent of p53. Both Mdm2 and mdmx inhibit DNA break repair through their association with the Mrell/RadSO/Nbs1 DNA repair complex. Recent evidence indicates that harnessing Mdm2 and/or mdmx-mediated inhibition of DNA break repair in cancer cells could provide a therapeutic opportunity, particularly for those malignancies that have lost functional p53.

关键词： Mdm2 mdmx Nbsl DNA repair

AXL receptor signalling suppresses p53 in melanoma through stabilization of the mdmx-MDM2 complex

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Journal of Molecular Cell Biology 2017年第2期9卷 154-165页

作者： Anna de Polo Zhongling Luot Casimiro Gerarduzzi Xiang Chen John B. Little Zhi-Min Yuan John B. Little Center for Radiation Sciences Harvard T.H. Chan School of Public Health Boston MA 02115 USA Department of Dermatology Xiangya Hospital Central South University Changsha 410008 China

Deregulation of the tyrosine kinase signalling is often associated with tumour progression and drug resistance, but its underlying mechanisms are only partly understood. In this study, we investigated the effects of the receptor tyrosine kinase AXL on the sta- biUty of the mdmx-MDM2 heterocomplex and the activity of p53 in melanoma cells. Our data demonstrated that AXL overexpres- sion or activation through growth arrest-specific 6 （Gas6） Ugand stimulation increases mdmx and MDM2 protein levels and decreases p53 activity. Upon activation, AXL stabilizes mdmx through a post-translational modification that involves phosphoryl- ation of mdmx on the phosphosite Ser314, leading to increased affinity between mdmx and MDM2 and favouring mdmx nuclear translocation. Ser314 phosphorylation can also protect mdmx from MDM2-mediated degradation, leading to stabilization of the mdmx-MDM2 complex. We identified CDK4/6 and p38 MAPK as the two kinases mediating AXL-induced modulation of the mdmx-MDM2 complex, and demonstrated that suppression of AXL, either through siRNA silencing or pharmacological inhibition, increases expression levels of p53 target genes P21, MDM2, and PUMA, improves p53 pathway response to chemotherapy, and sensitizes cells to both Cisplatin and Vemurafenib. Our findings offer an insight into a novel signalling axis linking AXL to p53 and provide a potentially druggable pathway to restore p53 function in melanoma.

关键词： mdmx MDM2 AXL CDK4/6 p53 melanoma

Bicyclic stapled peptides based on p53 as dual inhibitors for the interactions of p53 with MDM2 and mdmx

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Chinese Chemical Letters 2022年第3期33卷 1254-1258页

作者： Hongjin Li Xiangyan Chen Minghao Wu Panpan Song Xia Zhao Key Laboratory of Marine Drugs Ministry of EducationSchool of Medicine and PharmacyOcean University of ChinaQingdao 266003China Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology Qingdao 266237China

In recent years, the strategy of inhibiting the interactions of p53 with murine double minute 2(MDM2)and murine double minute X(mdmx) has been proved to be a promising approach for tumor ***, the poor proteolytical stability and low intracellular delivery efficiency of peptide inhibitors limit their clinical application. Here, we designed and synthesized the bicyclic stapled peptides based on p53 by combining all-hydrocarbon stapling and lactam stapling strategies. We demonstrated that bicyclic stapled peptide p53-16 significantly improved α-helicity and proteolytic stability. Especially, p53-16showed nanomolar binding affinity for MDM2 and mdmx. In addition, p53-16 could penetrate the cell membrane, and selectively inhibited the activity of tumor cells via activating p53 pathway in vitro. Our data suggest that p53-16 is a potential dual inhibitor of MDM2 and mdmx interactions. The bicyclic stapling strategy is a promising drug design strategy for protein–protein interactions inhibitors.

关键词： p53 MDM2 mdmx All-hydrocarbon stapling strategy Lactam stapling strategy Bicyclic stapling strategy

p53与MDM2及mdmx的相互作用和研究进展

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中国肿瘤临床 2012年第15期29卷 1123-1126页

作者：李小龙高明天津医科大学附属肿瘤医院甲状腺颈部肿瘤科天津市肿瘤防治重点实验室天津市300060

p53是重要的抑癌基因,在细胞周期阻滞、DNA损伤修复及细胞凋亡等生物过程中发挥重要作用,并已成为潜在的肿瘤治疗靶点。MDM2(Mdm2 p53 binding protein homolog)及mdmx(Mdm4 p53 binding protein homolog)是p53的主要抑制因子,两者相互... 详细信息

p53是重要的抑癌基因,在细胞周期阻滞、DNA损伤修复及细胞凋亡等生物过程中发挥重要作用,并已成为潜在的肿瘤治疗靶点。MDM2(Mdm2 p53 binding protein homolog)及mdmx(Mdm4 p53 binding protein homolog)是p53的主要抑制因子,两者相互协同并通过不同的信号途径抑制p53的活性。MDM2是p53的E3连接酶,介导p53的泛素化从而降低p53的稳定性。MD-MX则主要通过与p53的转录活性区结合,抑制p53对其下游基因的转录活性,但并不介导p53的降解。MDM2与mdmx通过不同机制协同对p53产生抑制作用,其具体分子过程及作用机制繁多且复杂。本文就p53。

关键词： p53 MDM2 mdmx 泛素化

mdmx小分子转录抑制剂的合成及其抗肿瘤活性评价

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MDMX小分子转录抑制剂的合成及其抗肿瘤活性评价

作者：冯玉鑫烟台大学

学位级别：硕士

背景与目的:鼠双微体X（Murine Double Minute X,mdmx）作为抑癌因子p53的天然抑制因子在神经胶质瘤和三阴性乳腺癌中均表现出高表达现象。本论文针对mdmx以及其抑制剂在恶性癌症治疗中的研究进展进行了综述,以mdmx选择性转录抑制剂XI-... 详细信息

背景与目的:鼠双微体X（Murine Double Minute X,mdmx）作为抑癌因子p53的天然抑制因子在神经胶质瘤和三阴性乳腺癌中均表现出高表达现象。本论文针对mdmx以及其抑制剂在恶性癌症治疗中的研究进展进行了综述,以mdmx选择性转录抑制剂XI-011为先导化合物进行设计、合成、表征及活性评价工作,筛选出了一系列效果优异的新型抗神经胶质瘤小分子抑制剂与抗三阴性乳腺癌小分子抑制剂。方法与结果:一、基于XI-011核心骨架的mdmx小分子转录抑制剂的开发基于XI-011结构的核心蒽环骨架对其进行设计,开发出一条简捷、高效的合成路线,完成了60个其结构衍生物的设计、合成及结构表征工作。使用MTT法对所有合成化合物进行了抗神经胶质瘤（U87）活性评价,成功筛选出5个IC值小于2μM的抑制剂,其中化合物2-14抗肿瘤效果最佳,IC值达到0.53μM。抗肿瘤机理实验证明化合物2-14可以有效减少U87细胞中的mdmx表达,上调细胞内p53水平,进而诱导肿瘤细胞凋亡,细胞周期和凋亡实验证实,化合物2-14可以有效诱导癌细凋亡,并使得U87细胞停滞在G2/M期。二、蒽基衍生的三苯基膦季磷盐化合靶向G-四链体以对抗三阴性乳腺癌的研究基于XI-011结构以及G-四链体结构特点,以XI-011为先导化合物设计、合成并表征了29个结构衍生化合物。通过MTT实验,对所合成化合物的抗三阴性乳腺癌（HCC1806,HCC1937,MDA-MB-231）活性进行了初步评价,并成功筛选出了6个效果优异的化合物,其中,化合物3-3对三种细胞系均拥有良好的抑制能力,其IC值分别为4.13μM、3.87μM、3.65μM。结合生物膜干涉技术实验结果,化合物3-3可以与靶向到mdmx/MDM2基因G-四链体结构,其K值分别为5.2μM、4.9μM,同时也证明了三苯基膦基团的引入以及溴原子的取代使蒽类化合物能够靶向到MDM蛋白基因G-四链体结构。创新性及结论:一、基于已有mdmx转录抑制剂XI-011骨架结构,对60个新化合物进行了设计、合成、结构表征、抗胶质瘤活性评价研究。成功筛选出了五个对神经胶质瘤细胞株U87具有良好生长抑制作用的新型抑制剂。特别是化合物2-14,对U87的IC值达到0.53μM。机理实验证明化合物2-14可以有效减少U87细胞中的mdmx表达,上调细胞内p53水平,使得U87细胞停滞在G2/M期,进而诱导细胞凋亡。本工作可以为抗胶质瘤新药的研发提供候选分子及新思路。二、基于XI-011结构以及G-四链体结构特点,设计、合成并表征了29个新化合物,并创新的向XI-011的蒽环核心结构引入三苯基膦基团与溴原子。通过MTT法筛选出对三阴性乳腺癌细胞具有抑制作用的6个化合物,其中化合物3-3三种三阴性乳腺癌细胞系（HCC1806,HCC1937,MDA-MB-231）均有良好抑制作用,其IC值分别达到了4.13μM、3.87μM、3.65μM。生物膜干涉技术实验证明,化合物3-3能够与mdmx/MDM2基因G-四链体结构结合,三苯基膦基团与溴原子的引入能够增强蒽类化合物靶向G-四链体的能力。本工作可以为抗三阴性乳腺癌的新药研发提供候选分子以及提供化合物靶向G-四链体的设计思路。

关键词： mdmx 神经胶质瘤三阴性乳腺癌先导化合物

mdmx通过14-3-3-γ/FOXO1影响肝癌发生发展的机制研究

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MDMX通过14-3-3-γ/FOXO1影响肝癌发生发展的机制研究

作者：林武福建医科大学

学位级别：硕士

研究背景:mdmx(MDM4)是p53最重要的负调控因子之一,与人类癌症的发生和发展有关。大量研究表明mdmx在各种人类癌症的发生发展中发挥着关键作用。mdmx不仅可以增强MDM2对p53的降解,还可以通过直接与p53结合抑制p53的功能,从而促进癌症的... 详细信息

研究背景:mdmx(MDM4)是p53最重要的负调控因子之一,与人类癌症的发生和发展有关。大量研究表明mdmx在各种人类癌症的发生发展中发挥着关键作用。mdmx不仅可以增强MDM2对p53的降解,还可以通过直接与p53结合抑制p53的功能,从而促进癌症的发生发展。越来越多的研究发现mdmx具有不依赖野生型p53的功能,有研究发现mdmx能促进肿瘤的发生,也有研究结果相反。研究目的:1.探讨mdmx对突变p53肝癌细胞生物学行为的影响;2.探讨mdmx对FOXO1表达的影响及其可能的分子机制。研究内容和研究方法:1.确定mdmx影响p53突变肝癌细胞系的生长。在Huh7细胞中转染mdmx质粒,采用CCK8检测试剂盒以及克隆形成实验检测Huh7细胞的增殖能力;2.敲低mdmx验证mdmx对于p53突变肝癌细胞系的生长的影响。采用sh RNA转染Huh7细胞敲低mdmx的蛋白表达水平,采用CCK8检测试剂盒以及克隆形成实验检测Huh7细胞的增殖能力;3.通过q-PCR与Western Blot实验探究mdmx是否影响FOXO1的表达;4.通过Western Blot以及免疫荧光实验探究mdmx是否影响FOXO1的定位;5.利用染色质免疫沉淀技术探究mdmx是否影响FOXO1下游的转录因子;6.利用免疫共沉淀技术探究筛选与mdmx与FOXO1相互作用的蛋白;7.利用免疫共沉淀技术探究mdmx对FOXO1和14-3-3-γ的影响;8.利用免疫共沉淀技术探究mdmx影响FOXO1和14-3-3-γ相互作用的结构域。结果1.与对照组相比,过表达mdmx蛋白会促进p53突变型肝癌细胞的生长,而敲低mdmx蛋白会抑制p53突变型肝癌细胞的生长。2.过表达mdmx会促进FOXO1蛋白的表达,但是mdmx不影响FOXO1的转录。3.过表达mdmx会改变FOXO1在细胞里的定位,mdmx会促进FOXO1定位在细胞核当中。***与FOXO1不会发生相互作用,但是mdmx与FOXO1均会与14-3-3-γ发生相互作用。5.免疫共沉淀实验确定mdmx可以促进FOXO1和14-3-3-γ的相互作用。***影响FOXO1和14-3-3-γ的相互作用可能与mdmx的C端结构域有关。结论***可以促进p53突变型肝癌的发生发展。***通过促进FOXO1入核增强肿瘤细胞的增殖能力。3.14-3-3-γ调节FOXO1的定位及功能。4.14-3-3-γ介导mdmx促进FOXO1入核的调控,且与mdmx的C端结构域密切相关。

关键词： mdmx FOXO1 p53突变肝细胞癌

mdmx转录抑制剂抗恶性脑胶质瘤的药效学评价及机制研究

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MDMX转录抑制剂抗恶性脑胶质瘤的药效学评价及机制研究

作者：汪英杰烟台大学

学位级别：硕士

背景与目的:恶性脑胶质瘤(Glioblastoma,GBM)是神经胶质瘤中恶性程度最高的一类亚型,发病率约占颅内原发肿瘤的40%且呈逐年升高趋势,具有死亡率高、预后差等特征,严重威胁人类的健康。现有GBM治疗方式局限于手术及放化疗,难以治愈。针... 详细信息

背景与目的:恶性脑胶质瘤(Glioblastoma,GBM)是神经胶质瘤中恶性程度最高的一类亚型,发病率约占颅内原发肿瘤的40%且呈逐年升高趋势,具有死亡率高、预后差等特征,严重威胁人类的健康。现有GBM治疗方式局限于手术及放化疗,难以治愈。针对其特异性靶标的发现及活性分子的开发对于靶向GBM药物的研发至关重要。鼠双微体X(Murine Double Minute X,mdmx)是驱动肿瘤恶性化的重要因子,在GBM细胞普遍高表达,化学靶向mdmx在脑胶质瘤中的潜在抗肿瘤活性尚不明确。烟酰胺N-甲基转移酶(Nicotinamide-N-Methyltransferase,NNMT)是调控肿瘤细胞中基因表达的关键因子,同样在GBM细胞中高表达并促进其恶性化加剧,是GBM临床诊断和治疗的潜在靶标,但相关作用机制尚未阐明。本研究前期发现mdmx转录抑制剂XI-011,通过抑制mdmx转录活性激活p53的活性,从而发挥抗肿瘤活性,为以mdmx为治疗靶点并以此开发新型有效的抗恶性脑胶质瘤药物提供前期依据。方法和结果:1、XI-011抗恶性脑胶质瘤细胞水平的活性评价本研究自主合成化合物XI-011,通过MTT实验、细胞生长曲线实验、集落形成实验和WB实验证实XI-011能够抑制恶性脑胶质瘤细胞的增殖、抑制GBM细胞内mdmx蛋白的表达并激活野生型p53蛋白的表达。2、XI-011体内抗恶性胶质瘤细胞活性评价取健康C57BL/6小鼠腹腔注射给予10 mg/kg的XI-011,分别于不同时间节点采集血样和组织样本,通过LC-MS检测显示XI-011腹腔给药可快速吸收进入循环,并能透过血脑屏障进入脑组织。建立BALB/c裸鼠体内异位移植瘤模型,随机分为Control组、替莫唑胺组(50mg/kg)、XI-011组(10 mg/kg)、XI-011联合替莫唑胺组。实验结果显示XI-011单用可有效抑制体内恶性脑胶质瘤细胞生长,联合替莫唑胺可增强其抗肿瘤活性。3、XI-011抗恶性脑胶质瘤相关机制研究本研究通过分子对接、生物膜干涉技术、基因沉默技术、q RT-PCR、WB及双荧光素酶报告基因技术发现并鉴定NNMT是mdmx蛋白的上游转录因子并促进GBM细胞内mdmx蛋白的表达。通过Pull-down、基因沉默、WB、q RT-PCR、双荧光素酶报告基因及技术发现并鉴定了NNMT调控mdmx蛋白表达的中间转录因子MYH9,机制研究表明NNMT蛋白通过转录因子间接调控mdmx蛋白的表达而发挥抗恶性脑胶质瘤的作用。研究结论:本研究自行合成化合物XI-011,药效学评价发现该化合物XI-011体内外具有良好的抗恶性脑胶质瘤活性;药代动力学研究发现化合物XI-011能有效的透过血脑屏障;机制研究发现化合物XI-011结合NNMT蛋白,通过转录因子间接影响mdmx的转录,从而发挥抗恶性脑胶质瘤作用。

关键词： mdmx 转录调控抑制剂 NNMT 恶性脑胶质瘤