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1 Animal Sciences, University of Illinois, Urbana, IL, USA
2 Animal Sciences, University of Illinois, Urbana, IL, USA; Veterinary Pathology, University of Illinois, Urbana, IL, USA; Institute for Genomic Biology, University of Illinois, Urbana, IL, USA
* To whom correspondence should be addressed. E-mail: hgaskins{at}uiuc.edu.
The intracellular reduction-oxidation (redox) environment influences cell cycle progression; however, underlying mechanisms are poorly understood. To examine potential mechanisms, the intracellular redox environment was characterized per cell cycle phase in Chinese hamster ovary fibroblasts via flow cytometry by measuring reduced glutathione (GSH), reactive oxygen species (ROS), and DNA content with monochlorobimane, H2DCFDA, and DRAQTMrespectively. GSH content was significantly greater in G2/M compared to G1 phase cells, while GSH was intermediate in S phase cells. ROS content was similar among phases. Together, these data demonstrate that G2/M cells are more reduced than G1 cells. Conventional approaches to define regulatory mechanisms are subjective in nature and focus on single proteins/pathways. Proteome databases provide a means to overcome these inherent limitations. Therefore, a novel bioinformatic approach was developed to exhaustively identify putative redox-regulated cell cycle proteins containing redox-sensitive protein motifs. Using the InterPro (www.ebi.ac.uk/interpro/) database, 536 redox-sensitive motifs were categorized as: 1) active/functional-site cysteines (AC); 2) electron transport; 3) heme (H); 4) iron-binding (FeB); 5) zinc-binding (ZnB); 6) metal-binding (MeB; non-Fe/Zn); and 7) disulfides (SS). Comparing this list with 1634 cell cycle-associated proteins from SWISSPROT (www.ebi.ac.uk/swissprot/index.html) and SpTrEMBL (www.expasy.org/sprot/) revealed 92 candidate proteins. Three-fourths (69 of 92) of the candidate proteins function in the central cell cycle processes of transcription, nucleotide metabolism, (de)phosphorylation, and (de)ubiquitinylation. The majority of oxidant-sensitive candidate proteins (68.9%) function during G2/M phase. As the G2/M phase is more reduced than the G1 phase, oxidant-sensitive proteins may be temporally regulated by oscillation of the intracellular redox environment. Combined with evidence of intracellular redox compartmentalization, we propose a spatiotemporal mechanism that functionally links an oscillating intracellular redox environment with cell cycle progression.
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