Wang Lihong, Fraley Cresson D, Faridi Jesika, Kornberg Arthur, Roth Richard A
Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, CA 94305-5174, USA.
Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11249-54. doi: 10.1073/pnas.1534805100. Epub 2003 Sep 11.
Inorganic polyphosphate (poly P), chains of hundreds of phosphate residues linked by "high-energy" bonds as in ATP, has been conserved from prebiotic times in all cells. Poly P is essential for a wide variety of functions in bacteria, including virulence in pathogens. In this study, we observe the unique and many-fold stimulation by poly P in vitro of the protein kinase mTOR (mammalian target of rapamycin). To explore the role of poly P in mammalian cells, a yeast polyphosphatase, PPX1, was inserted into the chromosomes of MCF-7 mammary cancer cells. The transfected cells are markedly deficient in their response to mitogens, such as insulin and amino acids, as seen in their failure to activate mTOR to phosphorylate one of its substrates, PHAS-I (the initiation factor 4E-binding protein). In addition, the transfected cells are severely reduced in their growth in a serum-free medium. On the basis of these findings, we suggest that poly P (and/or PPX1) serves as a regulatory factor in the activation of mTOR in the proliferative signaling pathways of animal cells.
无机多聚磷酸盐（多聚P）是由数百个磷酸残基通过类似ATP中的“高能”键连接而成的链状结构，自前生物时代起在所有细胞中都得以保留。多聚P对细菌的多种功能至关重要，包括病原体的毒力。在本研究中，我们观察到多聚P在体外对蛋白激酶mTOR（雷帕霉素的哺乳动物靶点）具有独特且多重的刺激作用。为了探究多聚P在哺乳动物细胞中的作用，将一种酵母多聚磷酸酶PPX1插入MCF - 7乳腺癌细胞的染色体中。转染后的细胞对诸如胰岛素和氨基酸等有丝分裂原的反应明显不足，表现为无法激活mTOR使其磷酸化其底物之一PHAS - I（起始因子4E结合蛋白）。此外，转染后的细胞在无血清培养基中的生长严重受限。基于这些发现，我们认为多聚P（和/或PPX1）在动物细胞增殖信号通路中作为mTOR激活的调节因子发挥作用。
