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Differential regulation of H3S10 phosphorylation, mitosis progression and cell fate by aurora kinase B and C in mouse preimplantation embryos

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Protein & Cell 2017年第9期8卷 662-674页

作者： Wenzhi Li Peizhe Wang Bingjie Zhang Jing Zhang Jia Ming Wei Xie Jie Na Center for Stem Cell Biology and Regenerative Medicine School of Medicine Tsinghua University Beijing 100084 China Center for Stem Cell Biology and Regenerative Medicine MOE Key Laboratory of Bioinformatics THU-PKU Center for LifeSciences School of Life Sciences Tsinghua University Beijing 100084 China

Coordination of cell division and cell fate is crucial for the successful development of mammalian early embryos. aurora kinases are evolutionarily conserved serine/threonine kinases and key regulators of mitosis. aurora kinase B （AurkB） is ubiquitously expressed while aurora kinase C （AurkC） is specifically expressed in gametes and preimplantation embryos. We found that increasing AurkC level in one blastomere of the 2-cell embryo accelerated cell division and decreasing AurkC level slowed down mitosis. Changing AurkB level had the opposite effect. The kinase domains of AurkB and AurkC were responsible for their different ability to phosphorylate Histone H3 Serine 10 （H3S10P） and regulate metaphase timing. Using an Oct4-photoactivat- able GFP fusion protein （Oct4-paGFP） and fluorescence decay after photoactivation assay, we found that AurkB overexpression reduced Oct4 retention in the nucleus. Finally, we show that blastomeres with higher AurkC level elevated pluripotency gene expression, which were inclined to enter the inner cell mass lineage and subsequently contributed to the embryo proper. Collectively, our results are the first demonstration that the activity of mitotic kinases can influence cell fate decisions in mammalian preimplantation embryos and have important implications to assisted reproduction.

关键词： aurora kinase mouse preimplantation embryo cell fate development mitosis

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aurora kinase B and C have Distinct Functions of in Mouse Oocytes and Preimplantation Embryos.

Aurora Kinase B and C have Distinct Functions of in Mouse Oo...

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“细胞活动生命活力”——中国细胞生物学学会全体会员代表大会暨第十二次学术大会

作者： Wenzhi Li,Jie Na School of Medicine,Tsinghua University,Beijing,China

During mammalian oocyte meiosis and preimplantation development,abnormal cell division happens frequently and can lead to serious defect in the *** kineses are evolutionarily conserved serine/threonine kinase playing important roles during cell *** found that the mammalian germ cell specific aurora kinase C is highly expressed in mouse oocyes and preimplantation *** siRNA and specific chemical inhibitor,we investigate the function of aurora C and its close homologue, aurora B,in these ***,knocking down aurora B or C differentially affected securin degradation and the timing of cell division,while their overexpression had the opposite *** C knocking down delayed the timing of homologous separation,and this can not be rescued by aurora B overexpression,suggesting that they have distinct roles in spindle assembly checkpoint(SAC). Moreover,dominant negative MAD1 were also unable to override the SAC activation caused by knocking down aurora C,implying that it is down stream of MAD2 and a critical component of *** results indicate that the balance between aurora B and aurora C may regulate the timing of cell division in mouse oocytes and preimplantation embryos.

关键词： aurora kinase mouse oocyte preimplantation embryo

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aurora kinase inhibitor CCT129202 reverses multidrug resistance by inhibiting the efflux function of multiple ATP-Binding Cassette Transporters

Aurora kinase inhibitor CCT129202 reverses multidrug resista...

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2011医学科学前沿论坛第十二届全国肿瘤药理与化疗学术会议

作者： Zhen-guo Liu~1,Yong-ju Liang~2,Li-sheng Zheng~2,Yan-jun Mi~2,Chao Cheng~1,Li-wu Fu~2 1 Department of Thoracic Surgery,The First Affiliated Hospital of Sun Yat-Sen University,Guangzhou 510080,China 2 State Key Laboratory of Oncology in Southern China,Cancer Center,Sun Yat-Sen University,Guangzhou 510060,China

Background:ATP-Binding Cassette(ABC) Transporters play an important role in multidrug resistance(MDR),which can actively extrude a variety of chemotherapeutic drugs out of cancer cells leading to the fail of cancer *** this study,we examined the effect of CCT129202,a new aurora kinase inhibitor,on the reversal of multidrug resistance in vitro.

关键词： CCT129202 aurora kinase Multidrug resistance ATP-binding cassette transporters ABCB1/P-glycoprotein ABCG2/BCRP

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Computational Study on the Selectivity Mechanism of MLN8054 to aurora kinase A and B Subtypes by Molecular Dynamics Simulation and Free Energy Calculation

Computational Study on the Selectivity Mechanism of MLN8054 ...

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第十一届全国计算（机）化学学术会议

作者：杨颖刘焕香姚小军 State Key Laboratory of Applied Organic Chemistry and Department of Chemistry Lanzhou UniversityLanzhou 730000China School of Pharmacy Lanzhou UniversityLanzhou730000China

＜正＞Because of the high conservation of ATP-binding sites in all kinases,the quest for selective kinase inhibitor has been increasingly urgent in recent *** aurora kinase family represents attractive targets in cancer therapy and several small molecule inhibitors targeting aurora kinase are undergoing clinical *** them,MLN8054 has been proved to be a selective aurora-A inhibitor,and it is currently being evaluated in phase I trial for patients with advanced solid tumors. But the detailed selectivity mechanism of MLN8054 towards aurora-A over aurora-B is still *** our work,this selectivity mechanism was investigated by molecular dynamics simulation and free energy *** predicted binding conformation and binding affinities of MLN8054 to aurora-A and aurora-B suggest key interaction for the inhibitory *** analyses on the structure and free energy decomposition can provide some information about the structural basis for selectivity *** results could be helpful for the rational design of selective inhibitors of aurora-A.

关键词： aurora kinase MLN8054 inhibitor selectivity Molecular Dynamics simulation MM-PBSA MM-GBSA

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Spatio-Temporal Expression Patterns of aurora kinases A, B in Mouse Zygotes during the First Mitosis

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Journal of Reproduction and Contraception 2011年第1期22卷 11-21页

作者： Jie ZHANG Lin XU Guo-li WANG Divya RANA Tong LIU Di-di WU Bing-zhi YU Department of Biochemistry and Molecular Biology China Medical University Shenyang 110001 China Department of Gynecology and Obstetrics Shengjing Hospital of China Medical University Shenyang110003 China

Objective To investigate the expression and localization of aurora kinase A （A URKA ） and aurora kinase B （A URKB） in mouse zygotes during the process of the first mitosis. Methods Quantitative real-time RT-PCR and Western blotting were performed to analyze the expression of AURKA and AURKB. The subcellular location of AURKA and A URKB was studied by confocal microscopy. Results A URKA and A URKB were increasingly expressed from phase G1 and peaked at phase M. After the entrance into mitosis A URKB became the predominant form both in mRNA and protein levels. The proteins of A URKA and A URKB both distributed in the cytoplasm and were associated with nucleus during the first mitosis of mouse zygotes, with some details in different. Conclusion The expression and localization of aurora kinases A and B was in a cell- cycle regulated manner during the process of the cleavage of mouse zygotes. This discovery will aid in future investigations on their specific roles and molecular mecha- nisms in the regulation of mammalian early embryonic development.

关键词： aurora kinase mouse zygote localization cell cycle regulation

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Matrine and CYC116 Synergistically Inhibit Growth and Induce Apoptosis in Multiple Myeloma Cells

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Chinese Journal of Integrative Medicine 2015年第8期21卷 635-639页

作者：周郁鸿冯尽意尤良顺孟海涛钱文斌 The First Affiliated Hospital of Zhejiang Chinese Medical University Institute of Hematology the First Affiliated HospitalCollege of MedicineZhejiang University

Objective： To investigate whether CYC116 can potentiate matdne-dependent growth inhibition and apoptosis in multiple myeloma （MM） cells. Methods： The dose response relationship of matrine to dexamethasone-resistant and dexamethasone-sensitive MM cells was first established. Myeloma RPMI8226 cells were treated with matrine alone or combined with CYC116 for 24 h. Cell proliferation was measured using an M＇I-F assay and apoptosis induction was evaluated by flow cytometry. Activation ot the caspase pathway and expression of apoptosis regulator proteins were detected by Western blotting. Results： Matrine significantly induced growth arrest and apoptosis in both drug-resistant and drug-sensitive MM cells. Treatment with the combination of matrine and CYC116 had a stronger cytotoxic effect on MM cells than did single drug treatments. Enhanced apoptosis observed following the combined treatment of matrine and CYC116 was associated with higher levels of activation of caspase-9, caspase-3, and poly adenosine diphosphate ribose polymerase （PARP） and down-regulation of the anti-apoptotic proteins Bcl-2 and Mcl-1 and the signaling proteins p-Akt and nuclear factor K B （NF-κB）. Conclusions： CYC116 enhances the growth inhibitory and apoptotic effects of matrine on MM cells.

关键词： apoptosis aurora kinase CYC116 inhibitor matrine multiple myeloma

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