regulation of mtorc1 signaling by phmtorc1信号调节ph值.pdfVIP

Regulation of mTORC1 Signaling by pH 1 1 1 1 1¤ Aruna D. Balgi , Graham H. Diering , Elizabeth Donohue , Karen K. Y. Lam , Bruno D. Fonseca , Carla 1 1 1,2 Zimmerman , Masayuki Numata , Michel Roberge * 1 Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada, 2 The Centre for Drug Research and Development, Vancouver, British Columbia, Canada Abstract Background: Acidification of the cytoplasm and the extracellular environment is associated with many physiological and pathological conditions, such as intense exercise, hypoxia and tumourigenesis. Acidification affects important cellular functions including protein synthesis, growth, and proliferation. Many of these vital functions are controlled by mTORC1, a master regulator protein kinase that is activated by various growth-stimulating signals and inactivated by starvation conditions. Whether mTORC1 can also respond to changes in extracellular or cytoplasmic pH and play a role in limiting anabolic processes in acidic conditions is not known. Methodology/Findings: We examined the effects of acidifying the extracellular medium from pH 7.4 to 6.4 on human breast carcinoma MCF-7 cells and immortalized mouse embryo fibroblasts. Decreasing the extracellular pH caused intracellular acidification and rapid, graded and reversible inhibition of mTORC1, assessed by measuring the phosphorylation of the mTORC1 substrate S6K. Fibroblasts deleted of the tuberou