0 引言
Shvarts et al[1]报告了一种与p53蛋白结合蛋白的新基因,命名为MDMX,与MDM2蛋白在一级结构上具有同源性,特别是在p53蛋白结合域更是如此.另外,MDM2羧基末端的金属结合域在MDMX分子中也是高度保守的.MDMX蛋白又称为MDM4,是p53的...0 引言
Shvarts et al[1]报告了一种与p53蛋白结合蛋白的新基因,命名为MDMX,与MDM2蛋白在一级结构上具有同源性,特别是在p53蛋白结合域更是如此.另外,MDM2羧基末端的金属结合域在MDMX分子中也是高度保守的.MDMX蛋白又称为MDM4,是p53的一种结合蛋白,是p53蛋白的负调节因子.展开更多
本研究旨在探讨慢性淋巴细胞白血病(CLL)患者鼠双微体4(MDM4)基因mRNA的表达情况及其在CLL预后中的意义。采用SYBR Green I荧光染料行实时定量逆转录PCR(qRT-PCR)方法检测66例CLL患者白血病细胞MDM4 mRNA的表达,以β-actin为内参照物,以...本研究旨在探讨慢性淋巴细胞白血病(CLL)患者鼠双微体4(MDM4)基因mRNA的表达情况及其在CLL预后中的意义。采用SYBR Green I荧光染料行实时定量逆转录PCR(qRT-PCR)方法检测66例CLL患者白血病细胞MDM4 mRNA的表达,以β-actin为内参照物,以2(-△Ct)方法计算MDM4的相对定量值,组间分析采用秩和检验。结果显示,66例CLL患者MDM4 mRNA相对表达水平的中位数为0.037098(0.088245-0.014875);具有P53基因缺失的CLL患者,其MDM4的表达明显高于无P53基因缺失的患者(0.13167 vs 0.030927)(p<0.001),具有P53基因突变的CLL患者MDM4 mRNA表达也明显高于无P53基因突变的患者(0.13167 vs0.03077)(p<0.001);此外,MDM4 mRNA的表达水平还与Binet分期(p=0.044)和ATM基因缺失(p=0.046)显著相关,但与血清乳酸脱氢酶(LDH)(p=0.216)、β2-微球蛋白(β2-MG)(p=0.314)、胸苷激酶(TK)1(p=0.300)、ZAP-70(p=0.559)、CD38(p=0.513)和免疫球蛋白重链可变区(IgVH)基因突变状态(p=0.333)无显著相关性。结论:MDM4的表达与P53基因异常关系密切,与Binet分期和ATM基因缺失相关,MDM4可能在CLL的预后中具有重要价值。展开更多
Mdm2 and Mdm4 are two key negative regulators of the tumor suppressor p53.Deletion of either Mdm2 or Mdm4 induces p53-dependent early embryonic lethality in knockout mouse models.The tissuespecific deletion of Mdm2 in...Mdm2 and Mdm4 are two key negative regulators of the tumor suppressor p53.Deletion of either Mdm2 or Mdm4 induces p53-dependent early embryonic lethality in knockout mouse models.The tissuespecific deletion of Mdm2 induces p53-dependent apoptosis,whereas the deletion of Mdm4 induces both p53-dependent apoptosis and cell cycle arrest.Compared to Mdm4 deletion,Mdm2 deletion causes more severe phenotypic defects.Disrupting the Mdm2 and Mdm4 interaction using knockin mice models causes embryonic lethality that can be completely rescued by the concomitant loss of p53,suggesting that Mdm2 and Mdm4 heterodimerization is critical to inhibit p53 activity during embryogenesis.Overexpression of Mdm2 and Mdm4 in mice induces spontaneous tumorigenesis,which clearly indicates that Mdm2 and Mdm4 are bona fide oncogenes.Studies from these mouse models strongly suggest that blocking Mdm2and Mdm4-mediated p53 inhibition is an appealing therapeutic strategy for cancer patients with wild-type p53 alleles.展开更多
The mouse double minute 4(MDM4)is emerging from the shadow of its more famous relative MDM2 and is starting to steal the limelight,largely due to its therapeutic possibilities.MDM4 is a vital regulator of the tumor su...The mouse double minute 4(MDM4)is emerging from the shadow of its more famous relative MDM2 and is starting to steal the limelight,largely due to its therapeutic possibilities.MDM4 is a vital regulator of the tumor suppressor p53?It restricts p53 transcriptional activity and also,at least in development,facilitates MDM2's E3 ligase activity toward p53.These functions of MDM4 are critical for normal cell function and a proper response to stress.Their importance for proper cell maintenance and proliferation identifies them as a risk for deregulation associated with the uncontrolled growth of cancer.MDM4 tails are vital for its function,where its N-terminus transactivation domain engages p53 and its C-terminus RING domain binds to MDM2.In this review,we highlight recently identified cellular functions of MDM4 and survey emerging therapies directed to correcting its dys regulation in disease.展开更多
[目的]探讨化疗药物诱导肝癌细胞凋亡的潜在机制。[方法]高通量测序检测顺铂处理后肝癌细胞HepG2的失调miRNA。过表达失调miRNA后,检测HepG2的凋亡水平。miRDB在线分析和RNAi筛选鉴定miRNA的潜在底物。[结果]顺铂处理后,HepG2的凋亡水...[目的]探讨化疗药物诱导肝癌细胞凋亡的潜在机制。[方法]高通量测序检测顺铂处理后肝癌细胞HepG2的失调miRNA。过表达失调miRNA后,检测HepG2的凋亡水平。miRDB在线分析和RNAi筛选鉴定miRNA的潜在底物。[结果]顺铂处理后,HepG2的凋亡水平上升(18.23±3.01 vs 74.97±11.25,t=8.564,P<0.05)。过表达miR-301a-3p时,HepG2的凋亡水平上升(16.40±7.97 vs 56.12±9.37,t=5.590,P<0.05)。敲低miR-301a-3p时,HepG2的凋亡水平下降(21.34±3.34 vs 6.78±1.11,t=7.165,P<0.05)。敲低MDM4时,HepG2的凋亡水平上升(16.80±7.88 vs 72.85±10.70,t=7.302,P<0.05)。过表达MDM4时,HepG2的凋亡水平下降(19.11±5.02 vs 6.04±1.02,t=4.432,P<0.05)。过表达miR-301a-3p时,MDM4的mRNA水平和蛋白水平均下降(0.58±0.04 vs 0.11±0.01,t=19.74,P<0.05);而敲低miR-301a-3p时,MDM4的mRNA水平和蛋白水平均上升(0.58±0.04 vs 1.11±0.23,t=3.932,P<0.05)。肝癌组织中miR-301a-3p的表达水平显著低于癌旁组织(0.65±0.25 vs 0.40±0.04,t=5.949,P<0.05)。肝癌组织中MDM4的表达水平显著高于癌旁组织(0.036±0.025 vs 0.062±0.003,t=6.550,P<0.05)。同时,肝癌组织中miR-301a-3p和MDM4的表达水平呈现负相关(ρ=-0.385,P<0.05)。[结论]顺铂诱导肝癌细胞miR-301a-3p表达上调,miR-301a-3p通过靶向MDM4 mRNA的3’端非编码区,降解了MDM4 mRNA,减少了MDM4的蛋白表达,最终促进了肝癌细胞的凋亡。展开更多
Whilst most bioorthogonal reactions focus on targeting binding-site cysteine residues,proximity-induced reactivity effect ensures that reaction also occurs at nucleophilic lysine residues.We report one example here th...Whilst most bioorthogonal reactions focus on targeting binding-site cysteine residues,proximity-induced reactivity effect ensures that reaction also occurs at nucleophilic lysine residues.We report one example here that the propargylated-sulfonium center undergoes a nucleophilic reaction with lysine residue via proximity-induced conjugation.This propargylated-sulfonium tethered peptide resulting from a facile propargylation of thiolethers,enables amino-yne reaction at the selected lysine on MDM4 protein.This strategy represents a viable approach of lysine-targeted covalent inhibition in proximity.展开更多
In this article (p.240, MDM4 Inhibition section, second paragraph), the drug name of Aileron stapled peptide ‘ALN-6924’ was incorrectly cited (as ‘ALN-6942’). This mistake was due to human error. The conclusions o...In this article (p.240, MDM4 Inhibition section, second paragraph), the drug name of Aileron stapled peptide ‘ALN-6924’ was incorrectly cited (as ‘ALN-6942’). This mistake was due to human error. The conclusions of the review are not affected and the authors apologize for this error.展开更多
文摘0 引言
Shvarts et al[1]报告了一种与p53蛋白结合蛋白的新基因,命名为MDMX,与MDM2蛋白在一级结构上具有同源性,特别是在p53蛋白结合域更是如此.另外,MDM2羧基末端的金属结合域在MDMX分子中也是高度保守的.MDMX蛋白又称为MDM4,是p53的一种结合蛋白,是p53蛋白的负调节因子.
文摘本研究旨在探讨慢性淋巴细胞白血病(CLL)患者鼠双微体4(MDM4)基因mRNA的表达情况及其在CLL预后中的意义。采用SYBR Green I荧光染料行实时定量逆转录PCR(qRT-PCR)方法检测66例CLL患者白血病细胞MDM4 mRNA的表达,以β-actin为内参照物,以2(-△Ct)方法计算MDM4的相对定量值,组间分析采用秩和检验。结果显示,66例CLL患者MDM4 mRNA相对表达水平的中位数为0.037098(0.088245-0.014875);具有P53基因缺失的CLL患者,其MDM4的表达明显高于无P53基因缺失的患者(0.13167 vs 0.030927)(p<0.001),具有P53基因突变的CLL患者MDM4 mRNA表达也明显高于无P53基因突变的患者(0.13167 vs0.03077)(p<0.001);此外,MDM4 mRNA的表达水平还与Binet分期(p=0.044)和ATM基因缺失(p=0.046)显著相关,但与血清乳酸脱氢酶(LDH)(p=0.216)、β2-微球蛋白(β2-MG)(p=0.314)、胸苷激酶(TK)1(p=0.300)、ZAP-70(p=0.559)、CD38(p=0.513)和免疫球蛋白重链可变区(IgVH)基因突变状态(p=0.333)无显著相关性。结论:MDM4的表达与P53基因异常关系密切,与Binet分期和ATM基因缺失相关,MDM4可能在CLL的预后中具有重要价值。
文摘Mdm2 and Mdm4 are two key negative regulators of the tumor suppressor p53.Deletion of either Mdm2 or Mdm4 induces p53-dependent early embryonic lethality in knockout mouse models.The tissuespecific deletion of Mdm2 induces p53-dependent apoptosis,whereas the deletion of Mdm4 induces both p53-dependent apoptosis and cell cycle arrest.Compared to Mdm4 deletion,Mdm2 deletion causes more severe phenotypic defects.Disrupting the Mdm2 and Mdm4 interaction using knockin mice models causes embryonic lethality that can be completely rescued by the concomitant loss of p53,suggesting that Mdm2 and Mdm4 heterodimerization is critical to inhibit p53 activity during embryogenesis.Overexpression of Mdm2 and Mdm4 in mice induces spontaneous tumorigenesis,which clearly indicates that Mdm2 and Mdm4 are bona fide oncogenes.Studies from these mouse models strongly suggest that blocking Mdm2and Mdm4-mediated p53 inhibition is an appealing therapeutic strategy for cancer patients with wild-type p53 alleles.
文摘The mouse double minute 4(MDM4)is emerging from the shadow of its more famous relative MDM2 and is starting to steal the limelight,largely due to its therapeutic possibilities.MDM4 is a vital regulator of the tumor suppressor p53?It restricts p53 transcriptional activity and also,at least in development,facilitates MDM2's E3 ligase activity toward p53.These functions of MDM4 are critical for normal cell function and a proper response to stress.Their importance for proper cell maintenance and proliferation identifies them as a risk for deregulation associated with the uncontrolled growth of cancer.MDM4 tails are vital for its function,where its N-terminus transactivation domain engages p53 and its C-terminus RING domain binds to MDM2.In this review,we highlight recently identified cellular functions of MDM4 and survey emerging therapies directed to correcting its dys regulation in disease.
文摘[目的]探讨化疗药物诱导肝癌细胞凋亡的潜在机制。[方法]高通量测序检测顺铂处理后肝癌细胞HepG2的失调miRNA。过表达失调miRNA后,检测HepG2的凋亡水平。miRDB在线分析和RNAi筛选鉴定miRNA的潜在底物。[结果]顺铂处理后,HepG2的凋亡水平上升(18.23±3.01 vs 74.97±11.25,t=8.564,P<0.05)。过表达miR-301a-3p时,HepG2的凋亡水平上升(16.40±7.97 vs 56.12±9.37,t=5.590,P<0.05)。敲低miR-301a-3p时,HepG2的凋亡水平下降(21.34±3.34 vs 6.78±1.11,t=7.165,P<0.05)。敲低MDM4时,HepG2的凋亡水平上升(16.80±7.88 vs 72.85±10.70,t=7.302,P<0.05)。过表达MDM4时,HepG2的凋亡水平下降(19.11±5.02 vs 6.04±1.02,t=4.432,P<0.05)。过表达miR-301a-3p时,MDM4的mRNA水平和蛋白水平均下降(0.58±0.04 vs 0.11±0.01,t=19.74,P<0.05);而敲低miR-301a-3p时,MDM4的mRNA水平和蛋白水平均上升(0.58±0.04 vs 1.11±0.23,t=3.932,P<0.05)。肝癌组织中miR-301a-3p的表达水平显著低于癌旁组织(0.65±0.25 vs 0.40±0.04,t=5.949,P<0.05)。肝癌组织中MDM4的表达水平显著高于癌旁组织(0.036±0.025 vs 0.062±0.003,t=6.550,P<0.05)。同时,肝癌组织中miR-301a-3p和MDM4的表达水平呈现负相关(ρ=-0.385,P<0.05)。[结论]顺铂诱导肝癌细胞miR-301a-3p表达上调,miR-301a-3p通过靶向MDM4 mRNA的3’端非编码区,降解了MDM4 mRNA,减少了MDM4的蛋白表达,最终促进了肝癌细胞的凋亡。
基金financial support from the National Key Research and Development Program"Synthetic Biology"Key Special Project of China(No.2018YFA0902504)the Natural Science Foundation of China(Nos.21778009 and 21977010)+6 种基金the Natural Science Foundation ofGuangdongProvince(Nos.2020A1515010766,2020A1515010522,2019A1515111184 and 2019A1515110489)the Shenzhen Science and Technology Innovation Committee(Nos.JCYJ20180507181527112,JCYJ20180508152213145,and JCYJ20170817172023838)financial support from Beijing National Laboratory of Molecular Science Open Grant(No.BNLMS20160112)Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions(No.2019SHIBS0004)supported by Proteomic Platform of Pingshan Translational Medicine CenterShenzhen Bay Laboratorythe high-performance computing platform of Peking University.
文摘Whilst most bioorthogonal reactions focus on targeting binding-site cysteine residues,proximity-induced reactivity effect ensures that reaction also occurs at nucleophilic lysine residues.We report one example here that the propargylated-sulfonium center undergoes a nucleophilic reaction with lysine residue via proximity-induced conjugation.This propargylated-sulfonium tethered peptide resulting from a facile propargylation of thiolethers,enables amino-yne reaction at the selected lysine on MDM4 protein.This strategy represents a viable approach of lysine-targeted covalent inhibition in proximity.
文摘In this article (p.240, MDM4 Inhibition section, second paragraph), the drug name of Aileron stapled peptide ‘ALN-6924’ was incorrectly cited (as ‘ALN-6942’). This mistake was due to human error. The conclusions of the review are not affected and the authors apologize for this error.
