國家衛生研究院 NHRI:Item 3990099045/11778
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    题名: Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation
    作者: Chen, TJ;Wang, HJ;Liu, JS;Cheng, HH;Hsu, SC;Wu, MC;Lu, CH;Wu, YF;Wu, JW;Liu, YY;Kung, HJ;Wang, WC
    贡献者: Institute of Biotechnology and Pharmaceutical Research;Institute of Molecular and Genomic Medicine
    摘要: PKM2 is a key metabolic enzyme central to glucose metabolism and energy expenditure. Multiple stimuli regulate PKM2's activity through allosteric modulation and post-translational modifications. Furthermore, PKM2 can partner with KDM8, an oncogenic demethylase and enter the nucleus to serve as a HIF1alpha co-activator. Yet, the mechanistic basis of the exon-10 region in allosteric regulation and nuclear translocation remains unclear. Here, we determined the crystal structures and kinetic coupling constants of exon-10 tumor-related mutants (H391Y and R399E), showing altered structural plasticity and reduced allostery. Immunoprecipitation analysis revealed increased interaction with KDM8 for H391Y, R399E, and G415R. We also found a higher degree of HIF1alpha-mediated transactivation activity, particularly in the presence of KDM8. Furthermore, overexpression of PKM2 mutants significantly elevated cell growth and migration. Together, PKM2 exon-10 mutations lead to structure-allostery alterations and increased nuclear functions mediated by KDM8 in breast cancer cells. Targeting the PKM2-KDM8 complex may provide a potential therapeutic intervention.
    日期: 2019-03-15
    關聯: Communications Biology. 2019 Mar 15;2:Article number 105.
    Link to: http://dx.doi.org/10.1038/s42003-019-0343-4
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2399-3642&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000461240000003
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85065896674
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