Abstract
Yeast and cancer cells share the unusual characteristic of favoring fermentation of sugar over respiration. We now reveal an evolutionary conserved mechanism linking fermentation to activation of Ras, a major regulator of cell proliferation in yeast and mammalian cells, and prime proto-oncogene product. A yeast mutant (tps1∆) with overactive influx of glucose into glycolysis and hyperaccumulation of Fru1,6bisP, shows hyperactivation of Ras, which causes its glucose growth defect by triggering apoptosis. Fru1,6bisP is a potent activator of Ras in permeabilized yeast cells, likely acting through Cdc25. As in yeast, glucose triggers activation of Ras and its downstream targets MEK and ERK in mammalian cells. Biolayer interferometry measurements show that physiological concentrations of Fru1,6bisP stimulate dissociation of the pure Sos1/H-Ras complex. Thermal shift assay confirms direct binding to Sos1, the mammalian ortholog of Cdc25. Our results suggest that the Warburg effect creates a vicious cycle through Fru1,6bisP activation of Ras, by which enhanced fermentation stimulates oncogenic potency.
Highlights
Yeast and cancer cells share the unusual characteristic of favoring fermentation of sugar over respiration
We show that glucose addition to galactose-grown tps1Δ cells triggers rapid and dramatic activation of Ras, as opposed to the modest activation observed in wild type cells (Fig. 2a)
Since previous work had shown that the highly conserved C terminus of Cdc[25] was required for glucose activation of cAMP synthesis[38, 39], we focused on this part of Cdc[25] to identify amino acid residues of which mutagenesis might abolish Fru1,6bisP activation of Ras in permeabilized spheroplasts and restore growth of the tps1Δ mutant on glucose
Summary
Yeast and cancer cells share the unusual characteristic of favoring fermentation of sugar over respiration. We reveal an evolutionary conserved mechanism linking fermentation to activation of Ras, a major regulator of cell proliferation in yeast and mammalian cells, and prime proto-oncogene product. In spite of many studies, it remains controversial whether strong fermentation is a cause or a symptom of cancer since no clear molecular link between glycolysis and proteins controlling cell proliferation has been identified[5]. Ras serves as an important regulator of cell proliferation in yeast acting through activation of cAMP synthesis and the protein kinase A (PKA) pathway (Fig. 1)[6]. The strong conservation of Ras and its regulators, Cdc25,Sdc25/Sos[1] and Ira1,2/NF1, in yeast and mammalian cells, suggests that the unknown mechanism responsible for glycolytic activation of Ras may be conserved in the two cell types. Fru1,6bisP is split into the triose phosphates dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GAP), which are converted into pyruvate, and further into a fermentation product, either ethanol in yeast (Fig. 1) or lactic acid in mammalian cells
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