GABP couples oncogene signaling to telomere regulation in TERT promoter mutant cancer.
GABP couples oncogene signaling to telomere regulation in TERT promoter mutant cancer.
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DOI：
10.1016/j.celrep.2022.111344
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发表时间：
2022-09-20
期刊：
影响因子：
8.8
通讯作者：
Costello, Joseph F.
中科院分区：
文献类型：
--
作者：
McKinney, Andrew M.;Mathur, Radhika;Stevers, Nicholas O.;Molinaro, Annette M.;Chang, Susan M.;Phillips, Joanna J.;Costello, Joseph F.
端粒酶激活可以抵消由不受控制的增殖引起的衰老和端粒侵蚀。表皮生长因子受体 (EGFR) 扩增驱动增殖，而端粒酶逆转录酶启动子 (TERTp) 突变则通过招募 GA 结合蛋白 (GABP) 导致端粒酶重新激活。 EGFR 扩增和 TERTp 突变通常同时发生在胶质母细胞瘤中，胶质母细胞瘤是最常见和最具侵袭性的原发性脑肿瘤。为了确定这两种驱动增殖和永生的频繁改变是否在功能上相关，我们将来自肿瘤组织的拷贝数、mRNA 和蛋白质数据的分析与药理学和遗传扰动结合起来。我们证明增殖停滞以 GABP 依赖性方式降低 TERT 表达，并通过激活 AMP 介导的激酶 (AMPK) 和上调 GABP，选择性地从突变体 TERTp 中阐明从 EGFR 到 TERT 表达的关键增殖到永生途径。 EGFR-AMPK 信号传导促进端粒酶活性并维持端粒长度。这些结果定义了肿瘤细胞永生机制如何与持续的癌基因信号传导和细胞周期保持同步。 TERT 启动子突变在人类癌症中很常见，并赋予细胞永生性。麦金尼等人。描述胶质母细胞瘤中 TERT 启动子突变、EGFR 扩增和细胞周期之间的相互作用。结果表明，增殖驱动因素如何与端粒维持机制合作，抵消无限细胞分裂引起的端粒缩短。
Telomerase activation counteracts senescence and telomere erosion caused by uncontrolled proliferation. Epidermal growth factor receptor (EGFR) amplification drives proliferation while telomerase reverse transcriptase promoter (TERTp) mutations underlie telomerase reactivation through recruitment of GA-binding protein (GABP). EGFR amplification and TERTp mutations typically co-occur in glioblastoma, the most common and aggressive primary brain tumor. To determine if these two frequent alterations driving proliferation and immortality are functionally connected, we combine analyses of copy number, mRNA, and protein data from tumor tissue with pharmacologic and genetic perturbations. We demonstrate that proliferation arrest decreases TERT expression in a GABP-dependent manner and elucidate a critical proliferation-to-immortality pathway from EGFR to TERT expression selectively from the mutant TERTp through activation of AMP-mediated kinase (AMPK) and GABP upregulation. EGFR-AMPK signaling promotes telomerase activity and maintains telomere length. These results define how the tumor cell immortality mechanism keeps pace with persistent oncogene signaling and cell cycling. TERT promoter mutations are common in human cancer and confer cellular immortality. McKinney et al. describe the interaction between TERT promoter mutations, EGFR amplification, and the cell cycle in glioblastoma. The results demonstrate how proliferation drivers cooperate with telomere maintenance mechanisms to counteract telomere shortening caused by unlimited cell division.
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影响因子：
16.6
作者：
Han F;Li CF;Cai Z;Zhang X;Jin G;Zhang WN;Xu C;Wang CY;Morrow J;Zhang S;Xu D;Wang G;Lin HK
通讯作者：
Lin HK
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1056/nejmoa1407279
发表时间：
2015-06-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Eckel-Passow JE;Lachance DH;Molinaro AM;Walsh KM;Decker PA;Sicotte H;Pekmezci M;Rice T;Kosel ML;Smirnov IV;Sarkar G;Caron AA;Kollmeyer TM;Praska CE;Chada AR;Halder C;Hansen HM;McCoy LS;Bracci PM;Marshall R;Zheng S;Reis GF;Pico AR;O'Neill BP;Buckner JC;Giannini C;Huse JT;Perry A;Tihan T;Berger MS;Chang SM;Prados MD;Wiemels J;Wiencke JK;Wrensch MR;Jenkins RB
通讯作者：
Jenkins RB
影响因子：
15.9
作者：
Fouse, Shaun D.;Nakamura, Jean L.;Costello, Joseph F.
通讯作者：
Costello, Joseph F.
DOI：
10.1073/pnas.2008772118
发表时间：
2021-03-30
影响因子：
11.1
作者：
Amen AM;Fellmann C;Soczek KM;Ren SM;Lew RJ;Knott GJ;Park JE;McKinney AM;Mancini A;Doudna JA;Costello JF
通讯作者：
Costello JF