The cell cycle is a redox cycle: Linking phase-specific targets to cell fate

Reactive oxygen species (ROS) regulate the strength and duration of signaling through redox-dependent signal transduction pathways via the cyclic oxidation/reduction of cysteine residues in kinases, phosphatases, and other regulatory factors. Signaling circuits may be segregated in organelles or other subcellular domains with distinct redox states, permitting them to respond independently to changes in the oxidation state of two major thiol reductants, glutathione and thioredoxin. Studies in yeast, and in complex eukaryotes, show that oscillations in oxygen consumption, energy metabolism, and redox state are intimately integrated with cell cycle progression. Because signaling pathways play specific roles in different phases of the cell cycle and the hierarchy of redox-dependent regulatory checkpoints changes during cell cycle progression, the effects of ROS on cell fate vary during the cell cycle. In G1, ROS stimulate mitogenic pathways that control the activity of cyclin-dependent kinases (CDKs) and phosphorylation of the retinoblastoma protein (pRB), thereby regulating S-phase entry. In response to oxidative stress, Nrf2 and Foxo3a promote cell survival by inducing the expression of antioxidant enzymes and factors involved in cell cycle withdrawal, such as the cyclin-dependent kinase inhibitor (CKI) p27. In S phase, ROS induce S-phase arrest via PP2A-dependent dephosphorylation of pRB. In precancerous cells, unconstrained mitogenic signaling by activated oncogenes induces replication stress in S phase, which activates the DNA-damage response and induces cell senescence. A number of studies suggest that interactions of ROS with the G1 CDK/CKI network play a fundamental role in senescence, which is considered a barrier to tumorigenesis. Adaptive responses and loss of checkpoint proteins such as p53 and p16INK4a allow tumor cells to tolerate constitutive mitogenic signaling and enhanced production of ROS, leading to altered redox status in many fully transformed cells. Alterations in oxidant and energy metabolism of cancer cells have emerged as fertile ground for new therapeutic targets. The present challenge is to identify redox-dependent targets relevant to each cell cycle phase, to understand how these targets control fate decisions, and to describe the mechanisms that link metabolism to cell cycle progression.