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TRIB3 promotes pulmonary fibrosis through inhibiting SLUG degradation by physically interacting with MDM2

Acta Pharmaceutica Sinica B 2023年第4期13卷 1631-1647页

作者： Xiaoxi Lv Shanshan Liu Chang Liu Yunxuan Li Tingting Zhang Jie Qi Ke Li Fang Hua Bing Cui Xiaowei Zhang Yuxin Liu Jiaojiao Yu Jinmei Yu Li Li Xia Li Zhigang Yao Bo Huang State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China National Clinical Research Center for Metabolic Diseases Key Laboratory of Diabetes ImmunologyMinistry of EducationAnd Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangsha 410011China Drug Clinical Trial Institution Children's HospitalCapital Institute of PediatricsBeijing 100020China Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China Shandong University Weihai 264209China Department of Respiratory Medicine Beijing Friendship HospitalCapital Medical UniversityBeijing 100050China Institute of Basic Medicine Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100005China

Pulmonary fibrosis(PF)is the pathological structure of incurable fibroproliferative lung diseases that are attributed to the repeated lung injury-caused failure of lung alveolar regeneration(LAR).Here,we report that repetitive lung damage results in a progressive accumulation of the transcriptional repressor SLUG in alveolar epithelial type II cells(AEC2s).The abnormal increased SLUG inhibits AEC2s from self-renewal and differentiation into alveolar epithelial type I cells(AEC1s).We found that the elevated SLUG represses the expression of the phosphate transporter SLC34A2 in AEC2s,which reduces intracellular phosphate and represses the phosphorylation of JNK and P38 MAPK,two critical kinases supporting LAR,leading to LAR failure.TRIB3,a stress sensor,interacts with the E3 ligase MDM2 to suppress SLUG degradation in AEC2s by impeding MDM2-catalyzed SLUG ubiquitination.Targeting SLUG degradation by disturbing the TRIB3/MDM2 interaction using a new synthetic staple peptide restores LAR capacity and exhibits potent therapeutic efficacy against experimental PF.Our study reveals a mechanism of the TRIB3—MDM2—SLUG—SLC34A2 axis causing the LAR failure in PF,which confers a potential strategy for treating patients with fibroproliferative lung diseases.

关键词： E3 ligase Lung injury MDM2 Protein—protein interaction Proteolysis Ubiquitination UPS

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Extracellular and intracellular functions of coiled-coil domain containing 3

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Journal of Molecular Cell Biology 2023年第6期15卷 1-10页

作者： Sara Omari Hyemin Lee Jieqiong Wang Shelya X.Zeng Hua Lu Department of Biochemistry&Molecular Biology Tulane University School of MedicineNew OrleansLA 70112USA Tulane Cancer Center Tulane University School of MedicineNew OrleansLA 70112USA

Coiled-coil domain containing 3(CCDC3,also called Favine)is a highly conserved protein initially identified as a protein secreted from adipocytes and endothelial cells in the vascular system with endocrine-like functions.Recently,CCDC3 was also found to function as a nuclear tumor suppressor in breast cancers.Although it is still understudied,CCDC3,since its discovery,has been shown to play multiple roles in lipid metabolism,fatty liver,abdominal obesity,anti-inflammation,atherosclerosis,and cancer.This essay is thus composed to offer an overview of these extracellular endocrine-like and intracellular(nuclear)functions of CCDC3.We also discuss the possible underlying cellular and molecular mechanisms of CCDC3,the implications for clinical translation,and the remaining puzzles about this special molecule.

关键词： CCDC3 p53 MDM2 lipid metabolism p63 fatty liver(steatosis) tumor suppressor

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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 therapy.However, 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

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原发于直肠伴炎性肌纤维母细胞肿瘤样特征的去分化脂肪肉瘤1例

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中华病理学杂志 2023年第4期52卷 414-416页

作者：张春芳陈昊杨聪颖宋姗姗徐大洲张洪兰徐州医科大学附属连云港医院消化内科连云港222000 徐州医科大学附属连云港医院病理科连云港222000

伴炎性肌纤维母细胞肿瘤(inflammatory myofibroblastic tumor,IMT)样特征的去分化脂肪肉瘤(dedifferentiated liposarcoma,DDLPS)是一种罕见的以形态学类似IMT为特征的独特肿瘤。本文报道1例84岁女性患者原发于直肠的伴IMT样特征的DDL... 详细信息

伴炎性肌纤维母细胞肿瘤(inflammatory myofibroblastic tumor,IMT)样特征的去分化脂肪肉瘤(dedifferentiated liposarcoma,DDLPS)是一种罕见的以形态学类似IMT为特征的独特肿瘤。本文报道1例84岁女性患者原发于直肠的伴IMT样特征的DDLPS,组织学形态显示肿瘤主要由高分化脂肪肉瘤和IMT样特征的去分化成分2种成分组成,两者界限清楚,去分化区域肿瘤细胞梭形、多边形,束状或席纹状排列,间质疏松水肿的炎性背景,类似于IMT形态。免疫组织化学染色显示,去分化与高分化脂肪肉瘤成分均弥漫阳性表达波形蛋白、MDM2和p16,Ki-67阳性指数约10%(高分化脂肪肉瘤区域)和25%(伴有IMT样特征的去分化区域);CD117、CD34、DOG1、间变性淋巴瘤激酶(ALK)-1、结蛋白和广谱细胞角蛋白均阴性。荧光原位杂交(FISH)检测显示高分化脂肪肉瘤和IMT样特征的去分化区域均存在MDM2基因簇状扩增,而ALK-1基因重排阴性。具有IMT样特征的DDLPS与IMT相比,其生物学行为更具侵袭性,诊断除了免疫组织化学和FISH基因检测辅助手段外,仔细观察是否存在高分化脂肪肉瘤成分非常重要。

关键词：组织学形态阳性指数 CD117 基因重排 MDM2 免疫组织化学波形蛋白基因检测

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MDM2过表达诱导ALK阳性非小细胞肺癌克唑替尼耐药的实验研究

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陆军军医大学学报 2022年第24期44卷 2500-2506页

作者：刘嘉欣李姗姗王栋吕镗烽印洁宋勇叶明翔东部战区总医院呼吸与危重症医学科南京210002

目的探究MDM2过表达在间变性淋巴瘤激酶(anaplastic lymphoma kinase, ALK)突变的非小细胞肺癌(non-small cell lung cancer, NSCLC)H3122细胞中对克唑替尼敏感性的影响。方法通过转染MDM2质粒构建过表达MDM2蛋白的H3122 MDM2过表达... 详细信息

目的探究MDM2过表达在间变性淋巴瘤激酶(anaplastic lymphoma kinase, ALK)突变的非小细胞肺癌(non-small cell lung cancer, NSCLC)H3122细胞中对克唑替尼敏感性的影响。方法通过转染MDM2质粒构建过表达MDM2蛋白的H3122 MDM2过表达组细胞,对照组转染空载体构建H3122空载组细胞,给予不同浓度克唑替尼处理后进行MTT、平板克隆、TUNEL染色等实验评估MDM2表达状态对ALK靶向药物克唑替尼敏感性的影响。通过Western blot实验探究过表达MDM2后对ALK及其下游信号通路转导以及上皮间质转化过程(epithelial mesenchymal transition, EMT)标记物的影响。结果与H3122空载组细胞相比,H3122 MDM2过表达组细胞出现克唑替尼耐药表型,对药物诱导的细胞凋亡耐受,且过表达MDM2并不能维持ALK及其下游分子的磷酸化水平。过表达MDM2后,细胞发生EMT,获得间质细胞特征。结论过表达MDM2可能通过诱导EMT过程导致H3122细胞对克唑替尼耐药。

关键词： ALK靶向治疗克唑替尼耐药 MDM2 EMT

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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 treatment.Using 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 range.Here we report an ultrahigh affinity,dual-specificity peptide antagonist of MDM2 and mdmX obtained through systematic mutational analysis and additivitybased molecular design.Functional 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 calorimetry.Co-crystal structures of MDM2 and of mdmX in complex with PMI-M3 were solved at 1.65 and 3.0 A resolution,respectively.Similar 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 10.Notable 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 proteins.By 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 manner.This 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

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脂肪肉瘤中DDIT3荧光原位杂交分离探针判读陷阱及其意义分析

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中华病理学杂志 2022年第3期51卷 230-233页

作者：李锐叶胜兵赵明马恒辉陆珍凤饶秋夏秋媛解放军东部战区总医院病理科南京大学医学院临床学院南京210002

目的探讨脂肪肉瘤中DDIT3荧光原位杂交(FISH)分离探针判读陷阱及其意义。方法收集DDIT3端粒侧信号簇状扩增的脂肪肿瘤18例,回顾其HE形态、免疫组织化学及临床病理资料,加做MDM2、CDK4扩增FISH检测,结合临床资料、形态学、免疫学、分子... 详细信息

目的探讨脂肪肉瘤中DDIT3荧光原位杂交(FISH)分离探针判读陷阱及其意义。方法收集DDIT3端粒侧信号簇状扩增的脂肪肿瘤18例,回顾其HE形态、免疫组织化学及临床病理资料,加做MDM2、CDK4扩增FISH检测,结合临床资料、形态学、免疫学、分子结果对其重新诊断。结果18例DDIT3端粒侧信号扩增的脂肪肿瘤均应诊断为高分化脂肪肉瘤或去分化脂肪肉瘤,其MDM2、CDK4基因扩增FISH结果均为阳性。对照说明书探针设计细节并辅以MDM2、CDK4基因扩增FISH实验论证,发现DDIT3分离双色探针位于DDIT3基因两侧,均不覆盖DDIT3基因本身,而DDIT3基因及CDK4基因都位于第12号染色体长臂,距离很近,DDIT3分离探针的端粒侧探针覆盖CDK4基因;因此,当DDIT3分离探针不出现红绿信号分离结果,而覆盖CDK4基因的端粒侧信号出现簇状扩增,不能提示DDIT3基因存在异常,无法支持黏液样脂肪肉瘤/圆细胞脂肪肉瘤的诊断,反而能提示CDK4基因存在扩增改变,因此可支持高分化脂肪肉瘤/去分化脂肪肉瘤的诊断。结论基于临床工作观察,发现脂肪肉瘤中DDIT3 FISH分离探针判读存在陷阱,可能对脂肪肉瘤诊断产生误导。

关键词：脂肪肉瘤荧光原位杂交 MDM2 免疫组织化学信号分离端粒 CDK4 探针设计

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Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer

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Acta Pharmaceutica Sinica B 2021年第6期11卷 1617-1628页

作者： Shipeng He Junhui Ma Yuxin Fang Ying Liu Shanchao Wu Guoqiang Dong Wei Wang Chunquan Sheng Institute of Translational Medicine Shanghai UniversityShanghai 200444China School of Pharmacy Second Military Medical UniversityShanghai 200433China Department of Pharmacology and Toxicology and BIO5 Institute University of ArizonaTucsonAZ 85721USA School of Medicine Tongji UniversityShanghai 200072China

The dose-related adverse effects of MDM2-P5 3 inhibitors have caused significant concern in the development of clinical safe anticancer agents.Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2-P53 interaction.The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53.The new homo-PROTACs are designed to induce self-degradation of MDM2.The results of the investigation have shown that PROTAC 11 a efficiently dimerizes MDM2 with highly competitive binding activity and induces proteasome-dependent self-degradation of MDM2 in A549 non-small cell lung cancer cells.Furthermore,markedly,enantiomer 11 a-1 exhibits potent in vivo antitumor activity in A549 xenograft nude mouse model,which is the first example of homo-PROTAC with in vivo therapeutic potency.This study demonstrates the potential of the homo-PROTAC as an alternative chemical tool for tumorigenic MDM2 knockdown,which could be developed into a safe therapy for cancer treatment.

关键词： Homo-PROTAC MDM2 Self-degradation In vivo antitumor activity

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Murine double minute gene 2(MDM2)promoted hepatocellular carcinoma(HCC)cell growth by targeting fructose-1,6-bisphosphatase(FBP1)for degradation

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BIOCELL 2022年第6期46卷 1483-1491页

作者： YAO XU BIN WU JING YANG SHENG ZHANG LONGGEN LIU SUOBAO XU JIAKAI JIANG Department of Intensive Care Unit Changzhou No.3 People’s HospitalChangzhou213000China Department of General Surgery Changzhou No.3 People’s HospitalChangzhou213000China Department of Gastroenterology Changzhou No.1 People’s HospitalChangzhou213000China Department of Liver Disease Changzhou No.3 People’s HospitalChangzhou213000China

To study the roles and association of murine double minute gene 2(MDM2)and fructose-1,6-biphosphatase(FBP1)in human hepatocellular carcinoma(HCC),growth response of human HCC cells was assessed using proliferation and apoptosis assay.Pro-survival AKT signaling associated proteins(p-AKT,survivin and cleaved caspase 3)were assessed using western blotting.The correlation between MDM2 and FBP1 was assessed using coimmunoprecipitation combined with ubiquitination assay.Our data suggested that low expression of FBP1 was correlated with high levels of MDM2 in HCC cell lines(Huh7 and Hep3B).Overexpression of FBP1 resulted in antiproliferation,pro-apoptosis,the up-regulation of cleaved caspase 3 while the downregulation of survivin and phosphor(p)-AKT,however,knockdown of FBP1 led to the opposite.Furthermore,overexpression of MDM2 potently reversed FBP1-induced proliferation inhibition and apoptosis,while Nutlin-3(an MDM2 inhibitor)reversed the change trends induced by FBP1 knockdown in the aforementioned events.Lastly,but not least importantly,our data elucidated that MDM2 binds directly to FBP1 and promotes FBP1 ubiquitination.In conclusion,our data firstly suggested the involvement of FBP1 and its association with MDM2 in HCC cell growth.MDM2-FBP1-regulated HCC cell growth and the activation of AKT were mediated,at least in part,through FBP1 degradation.

关键词： Human hepatocellular carcinoma MDM2 FBP1 FBP1 ubiquitination

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FGFR/RACK1 interacts with MDM2, promotes P53 degradation, and inhibits cell senescence in lung squamous cell carcinoma

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Cancer Biology & Medicine 2021年第3期18卷 665-674页

作者： Tao Chen Fei Wang Shupei Wei Yingjie Nie Xiaotao Zheng Yu Deng Xubin Zhu Yuezhen Deng Nanshan Zhong Chengzhi Zhou State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China NHC Key Laboratory of Pulmonary Immunological Diseases Clinical Research Lab CenterGuizhou Provincial People’s HospitalGuiyang OK 550002China Longgang Central Hospital of Shenzhen Affiliated Shenzhen Longgang Central Hospital of Zunyi Medical CollegeShenzhen 518116China Center for Molecular Medicine Xiangya HospitalCentral South UniversityChangsha 410078China

Objective:FGFR is considered an important driver gene of lung squamous cell carcinoma(LSCC).Thus,identification of the biological events downstream of FGFR is important for the treatment of this malignancy.Our previous study has shown that the FGFR/RACK1 complex interacts with PKM2 and consequently promotes glycolysis in LSCC cells.However,the biological functions of the FGFR/RACK1 complex remain poorly understood.Methods:Anchorage-independent assays and in vivo tumorigenesis assays were performed to evaluate cancer cell malignancy.Distant seeding assays were performed to evaluate cancer cell metastasis.β-gal staining was used to examine cell senescence,and immunoprecipitation assays were performed to examine the interactions among FGFR,RACK1,and MDM2.Results:FGFR/RACK1 was found to regulate the senescence of LSCC cells.Treatment with PD166866,an inhibitor of FGFR,or knockdown of RACK1 induced senescence in LSCC cells(PMDM2 form a complex that promotes the degradation of p53 and thus inhibits cell senescence.PD166866 and RG7112,an MDM2/p53 inhibitor,cooperatively inhibited the colony formation and distal seeding of LSCC cells(P21.Conclusions:Together,our findings revealed the regulatory roles and mechanisms of FGFR/RACK1 in cell senescence.This understanding should be important in the treatment of LSCC.

关键词： FGFR RACK1 MDM2 P53 senescence

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