生物
下调和上调
视网膜母细胞瘤
磷酸化
基因敲除
癌症研究
视网膜母细胞瘤蛋白
NF-κB
αBκ
细胞周期
分子生物学
癌症
信号转导
细胞生物学
基因
生物化学
遗传学
作者
Xin Jin,Dongzhou Ding,Yuqian Yan,Hui Li,Bo Wang,Linlin Ma,Zhenqing Ye,Tao Ma,Qiang Wu,Daniel Nava Rodrigues,Manish Kohli,Rafael E. Jimenez,Liguo Wang,David W. Goodrich,Johann S. de Bono,Haidong Dong,Heshui Wu,Runzhi Zhu,Haojie Huang
出处
期刊:Molecular Cell
[Elsevier]
日期:2019-01-01
卷期号:73 (1): 22-35.e6
被引量:175
标识
DOI:10.1016/j.molcel.2018.10.034
摘要
Aberrant expression of programmed death ligand-1 (PD-L1) in tumor cells promotes cancer progression by suppressing cancer immunity. The retinoblastoma protein RB is a tumor suppressor known to regulate the cell cycle, DNA damage response, and differentiation. Here, we demonstrate that RB interacts with nuclear factor κB (NF-κB) protein p65 and that their interaction is primarily dependent on CDK4/6-mediated serine-249/threonine-252 (S249/T252) phosphorylation of RB. RNA-seq analysis shows a subset of NF-κB pathway genes including PD-L1 are selectively upregulated by RB knockdown or CDK4/6 inhibitor. S249/T252-phosphorylated RB inversely correlates with PD-L1 expression in patient samples. Expression of a RB-derived S249/T252 phosphorylation-mimetic peptide suppresses radiotherapy-induced upregulation of PD-L1 and augments therapeutic efficacy of radiation in vivo. Our findings reveal a previously unrecognized tumor suppressor function of hyperphosphorylated RB in suppressing NF-κB activity and PD-L1 expression and suggest that the RB-NF-κB axis can be exploited to overcome cancer immune evasion triggered by conventional or targeted therapies.
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