Translation initiation factor eIF3a regulates glucose metabolism and cell proliferation via promoting small GTPase Rheb synthesis and AMPK activation.
Translation initiation factor eIF3a regulates glucose metabolism and cell proliferation via promoting small GTPase Rheb synthesis and AMPK activation.
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翻译起始因子eIF3a通过促进小GTP酶Rheb的合成和AMPK的激活来调节葡萄糖代谢和细胞增殖。
DOI：
10.1016/j.jbc.2022.102044
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发表时间：
2022-07
影响因子：
4.8
通讯作者：
Zhang, Jian-Ting
中科院分区：
文献类型：
--
作者：
Ma, Shijie;Dong, Zizheng;Huang, Yanfei;Liu, Jing-Yuan;Zhang, Jian-Ting
真核生物翻译起始因子3亚基A （eIF3a）是eIF3复合物的最大亚基，已被证明在恶性癌细胞中过表达，可能使其成为原癌基因。eIF3a过表达可促进癌细胞增殖，但有助于改善预后。虽然其对预后的贡献先前被证明是由于其抑制DNA损伤修复蛋白合成的功能，但仍不清楚eIF3a如何调节癌细胞增殖。在这项研究中，我们使用遗传学方法证明eIF3a通过磷酸化和激活amp激活的蛋白激酶α (AMPKα)在其激酶激活环的Thr172位点，通过调节葡萄糖代谢来控制细胞增殖。我们证明eIF3a主要通过控制小GTPase Rheb的合成来调节AMPK的激活，该酶在很大程度上独立于众所周知的AMPK上游肝激酶B1和Ca2+/钙调素依赖性蛋白激酶激酶2，也独立于雷帕霉素信号传导和葡萄糖水平的哺乳动物靶点。我们的研究结果表明，癌细胞中的葡萄糖代谢和增殖可能通过一种新的eIF3a-Rheb-AMPK信号轴进行翻译调节。
Eukaryotic translation initiation factor 3 subunit A (eIF3a), the largest subunit of the eIF3 complex, has been shown to be overexpressed in malignant cancer cells, potentially making it a proto-oncogene. eIF3a overexpression can drive cancer cell proliferation but contributes to better prognosis. While its contribution to prognosis was previously shown to be due to its function in suppressing synthesis of DNA damage repair proteins, it remains unclear how eIF3a regulates cancer cell proliferation. In this study, we show using genetic approaches that eIF3a controls cell proliferation by regulating glucose metabolism via the phosphorylation and activation of AMP-activated protein kinase alpha (AMPKα) at Thr172 in its kinase activation loop. We demonstrate that eIF3a regulates AMPK activation mainly by controlling synthesis of the small GTPase Rheb, largely independent of the well-known AMPK upstream liver kinase B1 and Ca2+/calmodulin-dependent protein kinase kinase 2, and also independent of mammalian target of rapamycin signaling and glucose levels. Our findings suggest that glucose metabolism in and proliferation of cancer cells may be translationally regulated via a novel eIF3a–Rheb–AMPK signaling axis.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
影响因子：
16
作者：
Banko, Max R.;Allen, Jasmina J.;Schaffer, Bethany E.;Wilker, Erik W.;Tsou, Peiling;White, Jamie L.;Villen, Judit;Wang, Beatrice;Kim, Sara R.;Sakamoto, Kei;Gygi, Steven P.;Cantley, Lewis C.;Yaffe, Michael B.;Shokat, Kevan M.;Brunet, Anne
通讯作者：
Brunet, Anne
影响因子：
11.4
作者：
Boudeau, J;Baas, AF;Alessi, DR
通讯作者：
Alessi, DR
影响因子：
2.2
作者：
Eom, Minseob;Han, Airi;Park, Kwang Hwa
通讯作者：
Park, Kwang Hwa
DOI：
10.1186/s13058-014-0420-z
发表时间：
2014-08-06
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Hindupur SK;Balaji SA;Saxena M;Pandey S;Sravan GS;Heda N;Kumar MV;Mukherjee G;Dey D;Rangarajan A
通讯作者：
Rangarajan A