TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential.
TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential.
复制标题
DOI：
10.1038/s41421-023-00567-7
复制
发表时间：
2023-08-08
期刊：
影响因子：
33.5
通讯作者：
Lv, Lei
中科院分区：
文献类型：
--
作者：
He, Jing;Lin, Mingen;Zhang, Xinchao;Zhang, Ruonan;Tian, Tongguan;Zhou, Yuefan;Dong, Wenjing;Yang, Yajing;Sun, Xue;Dai, Yue;Xu, Yue;Zhang, Zhenru;Xu, Ming;Lei, Qun-Ying;Xu, Yanping;Lv, Lei
肿瘤的发展涉及细胞生长（质量积累）和细胞增殖，是一个由多种信号通路相互作用控制的复杂过程。TET2主要作为DNA双加氧酶，通过氧化DNA中的5mC来调节基因表达和生物学功能，但是否在调节细胞生长中起作用尚不清楚。在这里，我们发现TET2抑制mTORC1信号，一个主要的生长控制，抑制细胞生长和促进自噬。从机制上讲，TET2通过mRNA氧化起到5mC“擦除剂”的作用，消除YBX1-HuR结合，促进尿素循环酶mRNA的衰变，从而负调控尿素循环和精氨酸的产生，从而抑制mTORC1信号传导。因此，tet2缺失的肿瘤细胞对mTORC1抑制更为敏感。我们的研究结果揭示了TET2在抑制mTORC1信号传导和抑制细胞生长方面的新功能，将TET2介导的mRNA氧化与细胞代谢和细胞生长控制联系起来。这些发现表明mTORC1抑制可能是治疗tet2缺陷肿瘤的一种可能方法。
Tumor development, involving both cell growth (mass accumulation) and cell proliferation, is a complex process governed by the interplay of multiple signaling pathways. TET2 mainly functions as a DNA dioxygenase, which modulates gene expression and biological functions via oxidation of 5mC in DNA, yet whether it plays a role in regulating cell growth remains unknown. Here we show that TET2 suppresses mTORC1 signaling, a major growth controller, to inhibit cell growth and promote autophagy. Mechanistically, TET2 functions as a 5mC “eraser” by mRNA oxidation, abolishes YBX1–HuR binding and promotes decay of urea cycle enzyme mRNAs, thus negatively regulating urea cycle and arginine production, which suppresses mTORC1 signaling. Therefore, TET2-deficient tumor cells are more sensitive to mTORC1 inhibition. Our results uncover a novel function for TET2 in suppressing mTORC1 signaling and inhibiting cell growth, linking TET2-mediated mRNA oxidation to cell metabolism and cell growth control. These findings demonstrate the potential of mTORC1 inhibition as a possible treatment for TET2-deficient tumors.
登录
查看更多内容
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
16
作者：
Nakagawa, Tadashi;Lv, Lei;Nakagawa, Makiko;Yu, Yanbao;Yu, Chao;D'Alessio, Ana C.;Nakayama, Keiko;Fan, Heng-Yu;Chen, Xian;Xiong, Yue
通讯作者：
Xiong, Yue
影响因子：
50.3
作者：
Moran-Crusio K;Reavie L;Shih A;Abdel-Wahab O;Ndiaye-Lobry D;Lobry C;Figueroa ME;Vasanthakumar A;Patel J;Zhao X;Perna F;Pandey S;Madzo J;Song C;Dai Q;He C;Ibrahim S;Beran M;Zavadil J;Nimer SD;Melnick A;Godley LA;Aifantis I;Levine RL
通讯作者：
Levine RL
影响因子：
11.2
作者：
Jin SG;Jiang Y;Qiu R;Rauch TA;Wang Y;Schackert G;Krex D;Lu Q;Pfeifer GP
通讯作者：
Pfeifer GP
DOI：
10.1126/science.1259472
发表时间：
2015-01-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Jewell JL;Kim YC;Russell RC;Yu FX;Park HW;Plouffe SW;Tagliabracci VS;Guan KL
通讯作者：
Guan KL