Phosphofructokinase 1 glycosylation regulates cell growth and metabolism.
Phosphofructokinase 1 glycosylation regulates cell growth and metabolism.
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DOI：
10.1126/science.1222278
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发表时间：
2012-08-24
期刊：
影响因子：
--
通讯作者：
Hsieh-Wilson LC
中科院分区：
文献类型：
--
作者：
Yi W;Clark PM;Mason DE;Keenan MC;Hill C;Goddard WA 3rd;Peters EC;Driggers EM;Hsieh-Wilson LC
癌细胞需要在不断变化的微环境中满足细胞快速生长的代谢需求。将细胞代谢重新编程为增殖的、有利于生存的途径的遗传机制已经得到了很好的报道。然而，翻译后机制能够使细胞代谢更快速、更可逆地适应蛋白质信号或环境感应系统，人们对此知之甚少。在这里，我们证明了翻译后修饰的O-连接β-N-乙酰氨基葡萄糖(O-GlcNAc)是糖代谢的关键代谢调节因子。O-GlcNAc是在磷酸果糖激酶1(PFK1)的Ser529处动态诱导的，以响应低氧。糖基化抑制了PFK1的活性，并通过磷酸戊糖途径(PPP)重定向糖酵解的葡萄糖流量，从而赋予癌细胞选择性生长优势。在Ser529位阻断PFK1的糖基化可降低体外癌细胞的增殖和体内肿瘤的形成。这些研究揭示了代谢酶和代谢途径调节的一种意想不到的机制，并确定了一种抗击癌症的新治疗方法。
Cancer cells need to meet the metabolic demands of rapid cell growth within a continually changing microenvironment. Genetic mechanisms for reprogramming cellular metabolism toward proliferative, pro-survival pathways are well-reported. However, post-translational mechanisms, which would enable more rapid, reversible adaptations of cellular metabolism in response to protein signaling or environmental sensing systems, are less well understood. Here we demonstrate that the post-translational modification O-linked β-N-acetylglucosamine (O-GlcNAc) is a key metabolic regulator of glucose metabolism. O-GlcNAc is dynamically induced at Ser529 of phosphofructokinase 1 (PFK1) in response to hypoxia. Glycosylation inhibits PFK1 activity and redirects the flux of glucose from glycolysis through the pentose phosphate pathway (PPP), thereby conferring a selective growth advantage to cancer cells. Blocking glycosylation of PFK1 at Ser529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. These studies reveal an unexpected mechanism for the regulation of metabolic enzymes and pathways, and pinpoint a new therapeutic approach for combating cancer.
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DOI：
10.1126/science.1211485
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anastasiou D;Poulogiannis G;Asara JM;Boxer MB;Jiang JK;Shen M;Bellinger G;Sasaki AT;Locasale JW;Auld DS;Thomas CJ;Vander Heiden MG;Cantley LC
通讯作者：
Cantley LC
影响因子：
7.4
作者：
Fuhrer, Tobias;Heer, Dominik;Zamboni, Nicola
通讯作者：
Zamboni, Nicola
影响因子：
2.9
作者：
Sidorenko, Yury;Wahl, Aljoscha;Reichl, Udo
通讯作者：
Reichl, Udo
影响因子：
64.8
作者：
Possemato, Richard;Marks, Kevin M.;Shaul, Yoav D.;Pacold, Michael E.;Kim, Dohoon;Birsoy, Kivanc;Sethumadhavan, Shalini;Woo, Hin-Koon;Jang, Hyun G.;Jha, Abhishek K.;Chen, Walter W.;Barrett, Francesca G.;Stransky, Nicolas;Tsun, Zhi-Yang;Cowley, Glenn S.;Barretina, Jordi;Kalaany, Nada Y.;Hsu, Peggy P.;Ottina, Kathleen;Chan, Albert M.;Yuan, Bingbing;Garraway, Levi A.;Root, David E.;Mino-Kenudson, Mari;Brachtel, Elena F.;Driggers, Edward M.;Sabatini, David M.
通讯作者：
Sabatini, David M.
影响因子：
14.8
作者：
Rexach, Jessica E.;Clark, Peter M.;Mason, Daniel E.;Neve, Rachael L.;Peters, Eric C.;Hsieh-Wilson, Linda C.
通讯作者：
Hsieh-Wilson, Linda C.