MDMX phosphorylation-dependent p53 downregulation contributes to an immunosuppressive tumor microenvironment  

作　　者：Bing Wang Chuan-Bian Lim Jiawei Yan Lizhen Li Jufang Wang John B.Little Zhi-Min Yuan 

机构地区：[1]Key Laboratory of Space Radiobiology of Gansu Province&Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences,Institute of Modern Physics,Chinese Academy of Sciences,Lanzhou,China [2]University of Chinese Academy of Sciences,Beijing,China [3]John B.Little Center for Radiation Sciences,Harvard T.H.Chan School of Public Health,Boston,MA,USA [4]Present address:School of Life Sciences and Technology,ShanghaiTech University,Shanghai,China

出　　处：《Journal of Molecular Cell Biology》2020年第9期713-722,共10页分子细胞生物学报（英文版）

基　　金：This work was supported in part by the Morningside Foundation,the Zhu Fund,and grants from the National Cancer Institute at the National Institutes of Health(RO1CA233558,R01CA167814,and R01CA125144)to Z.-M.Y.

摘　　要：A role of tumor-suppressive activity of p53 in the tumor microenvironment(TME)has been implicated but remains fairly understudied.To address this knowledge gap,we leveraged our MdmxS314A mice as recipients to investigate how implanted tumor cells incapacitate host p53 creating a conducive TME for tumor progression.We found that tumor cell-associated stress induced p53 downregulation in peritumor cells via an MDMX-Ser314 phosphorylation-dependent manner.As a result,an immunosuppressive TME was developed,as reflected by diminished immune cell infiltration into tumors and compromised macrophage M1 polarization.Remarkably,ablation of MDMX-Ser314 phosphorylation attenuated p53 decline in peritumor cells,which was associated with mitigation of immunosuppression and significant tumor growth delay.Our data collectively uncover a novel role of p53 in regulating the tumor immune microenvironment,suggesting that p53 restoration in the TME can be exploited as a potential strategy of anticancer therapy.

关 键 词：P53 MDMX tumor microenvironment immune cell infiltration macrophage polarization 

分 类 号：R73-3[医药卫生—肿瘤]