生物
NF-κB
细胞生物学
NFKB1型
信号转导
癌症研究
转录因子
生物化学
基因
作者
Xiongjun Wang,Ruilong Liu,Xiujuan Qu,Hua Yu,Huiying Chu,Yajuan Zhang,Wencheng Zhu,Xueyuan Wu,Hong Gao,Bangbao Tao,Wenfeng Li,Ji Liang,Guohui Li,Weiwei Yang
出处
期刊:Molecular Cell
[Elsevier BV]
日期:2019-08-22
卷期号:76 (1): 148-162.e7
被引量:151
标识
DOI:10.1016/j.molcel.2019.07.007
摘要
The rapid proliferation of cancer cells and dysregulated vasculature within the tumor leads to limited nutrient accessibility. Cancer cells often rewire their metabolic pathways for adaption to nutrient stress, and the underlying mechanism remains largely unknown. Glutamate dehydrogenase 1 (GDH1) is a key enzyme in glutaminolysis that converts glutamate to α-ketoglutarate (α-KG). Here, we show that, under low glucose, GDH1 is phosphorylated at serine (S) 384 and interacts with RelA and IKKβ. GDH1-produced α-KG directly binds to and activates IKKβ and nuclear factor κB (NF-κB) signaling, which promotes glucose uptake and tumor cell survival by upregulating GLUT1, thereby accelerating gliomagenesis. In addition, GDH1 S384 phosphorylation correlates with the malignancy and prognosis of human glioblastoma. Our finding reveals a unique role of α-KG to directly regulate signal pathway, uncovers a distinct mechanism of metabolite-mediated NF-κB activation, and also establishes the critical role of α-KG-activated NF-κB in brain tumor development.
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