Vaccinia-related kinase 2 variants differentially affect breast cancer growth by regulating kinase activity  

作　　者：SEUNG-HEE GWAK JUHYUN LEE EUNJI OH DOHYUN LEE WONSHIK HAN JONGMIN KIM KYONG-TAI KIM 

机构地区：[1]Department of Life Sciences,Pohang University of Science and Technology,Pohang,37673,Korea [2]R&D Center,NovMetaPharma Co.,Ltd.,Pohang,37668,Korea [3]Department of Surgery and Cancer Research Institute,Seoul National University College of Medicine,Seoul,03080,Korea [4]Generative Genomics Research Center,Global Green Research&Development Center,Handong Global University,Pohang,37554,Korea

出　　处：《Oncology Research》2024年第2期421-432,共12页肿瘤学研究（英文）

基　　金：supported by the BK21 FOUR funded by the Ministry of Education,Republic of Korea,the National Research Foundation of Korea(NRF-2022R1F1A1066642,RS-2023-00272063)grant funded by the Korean government(MSIT),and POSTECH Basic Science Research Institute Grant(NRF-2021R1A6A1A10042944).Research was also supported by funds donated by Dr.Jae Kyu Lee and Mr.Jason Gim.Following are results of a study on the“Leaders in INdustry-University Cooperation 3.0”Project,supported by the Ministry of Education and National Research Foundation of Korea.

摘　　要：Genetic information is transcribed from genomic DNA to mRNA,which is then translated into threedimensional proteins.mRNAs can undergo various post-transcriptional modifications,including RNA editing that alters mRNA sequences,ultimately affecting protein function.In this study,RNA editing was identified at the 499th base(c.499)of human vaccinia-related kinase 2(VRK2).This RNA editing changes the amino acid in the catalytic domain of VRK2 from isoleucine(with adenine base)to valine(with guanine base).Isoleucine-containing VRK2 has higher kinase activity than the valine-containing VRK2,which leads to an increase in tumor cell proliferation.Earlier we reported that VRK2 directly interacts with dystrobrevin-binding protein(dysbindin)and results in reducing its stability.Herein,we demonstrate that isoleucine-containing VRK2 decreases the level of dysbindin than valinecontaining VRK2.Dysbindin interacts with cyclin D and thereby regulates its expression and function.The reduction in the level of dysbindin by isoleucine-containing VRK2 further enhances the cyclin D expression,resulting in increased tumor growth and reduction in survival rates.It has also been observed that in patient samples,VRK2 level was elevated in breast cancer tissue compared to normal breast tissue.Additionally,the isoleucine form of VRK2 exhibited a greater increase in breast cancer tissue.Therefore,it is concluded that VRK2,especially dependent on the 167th variant amino acid,can be one of the indexes of tumor progression and proliferation.

关 键 词：VRK2 Kinase activity Breast cancer Tumor RNA editing Cell proliferation Cell growth 

分 类 号：R737.9[医药卫生—肿瘤]