xCT expression reduces the early cell cycle requirement for calcium signaling.
Calcium has long been recognized as an important regulator of cell cycle transitions although the mechanisms are largely unknown. A functional genomic screen has identified genes involved in the regulation of early cell cycle progression by calcium. These genes when overexpressed confer the ability to bypass the G1/S arrest induced by Ca(2+)-channel antagonists in mouse fibroblasts. Overexpression of the cystine-glutamate exchanger, xCT, had the greatest ability to evade calcium antagonist-induced cell cycle arrest. xCT carries out the rate limiting step of glutathione synthesis in many cell types and is responsible for the uptake of cystine in most human cancer cell lines. Functional analysis indicates that the cystine uptake activity of xCT overcomes the G1/S arrest induced by Ca(2+)-channel antagonists by bypassing the requirement for calcium signaling. Since cells overexpressing xCT were found to have increased levels and activity of the AP-1 transcription factor in G1, redox stimulation of AP-1 activity accounts for the observed growth of these cells in the presence of calcium channel antagonists. These results suggest that reduced calcium signaling impairs AP-1 activation and that xCT expression may directly affect cell proliferation.
Department of Biomedical Sciences, Gen*NY*Sis Center for Excellence in Cancer Genomics, University at Albany, State University of New York, Room 210, One Discovery Drive, Rensselaer, NY 12144-3456, United States.
Michele
M
Lastro
Antonis
A
Kourtidis
Kate
K
Farley
Douglas S
DS
Conklin
D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009543:Nifedipine / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010641:Phenotype; D016196:S Phase / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
D027182:Amino Acid Transport System y+; D002121:Calcium Channel Blockers; C118895:SLC7A11 protein, human; D013438:Sulfhydryl Compounds; D018808:Transcription Factor AP-1; D009543:Nifedipine; D002118:Calcium