Redox control of the cell cycle in health and disease

Abstract

The cellular oxidation and reduction (redox) environment is influenced by the production and removal of reactive oxygen species (ROS). In recent years, several reports support the hypothesis that cellular ROS levels could function as ''second messengers'' regulating numerous cellular processes, including proliferation. Periodic oscillations in the cellular redox environment, a redox cycle, regulate cell-cycle progression from quiescence (G(0)) to proliferation (G(1), S, G(2), and M) and back to quiescence. A loss in the redox control of the cell cycle could lead to aberrant proliferation, a hallmark of various human pathologies. This review discusses the literature that supports the concept of a redox cycle controlling the mammalian cell cycle, with an emphasis on how this control relates to proliferative disorders including cancer, wound healing, fibrosis, cardiovascular diseases, diabetes, and neurodegenerative diseases. We hypothesize that reestablishing the redox control of the cell cycle by manipulating the cellular redox environment could improve many aspects of the proliferative disorders.

FIG. 1.

ROS signaling and cellular processes. Reactive oxygen species (ROS; e.g., O₂^•− and H₂O₂) are produced intracellularly by the mitochondrial electron-transport chain and flavin-containing enzymes. Superoxide dismutase (MnSOD and CuZnSOD) converts O₂^•− to H₂O₂; catalase (CAT), peroxiredoxin (Prx), and glutathione (GSH)-glutathione peroxide (GPx) neutralize H₂O₂ to water. H₂O₂ in the presence of metals can generate hydroxyl radical (HO^•); HO^• damages cellular macromolecules. ROS can serve as second messengers influencing multiple signaling pathways that regulate proliferation, quiescence, differentiation, and cell death. The redox potentials related to these cellular processes were adapted from literature report (282).

FIG. 2.

A redox cycle within the cell cycle that is preserved in the daughter generations. The cell cycle has two distinct growth states: quiescence (G₀) and proliferation (G₁, S, G₂, and M). Progression through the cell cycle is regulated by cell-cycle phase–specific activation of cyclins and cyclin-dependent kinases (CDKs). In the G₁ phase, cyclin D1/CDK4-6 and cyclin E/CDK2 are the major regulators. Cyclin A/CDK2 and cyclin B/CDK1 regulate the S, G₂, and M phases. Cyclin/CDK complexes phosphorylate retinoblastoma (Rb) protein, which undergoes conformational change, releasing the transcription factor, E2F. E2F regulates transcription of S phase–specific genes. The periodicity in the cellular redox environment is represented by the line graph.

FIG. 3.

Thiol-redox reactions regulating CDC25 phosphatase activity. The reduced form of cysteine in proteins can undergo oxidation reactions to form sulfenic, sulfinic, and sulfonic acids. Sulfinic and sulfonic forms are believed to be irreversible, whereas the sulfenic form can conjugate with other reduced thiols (RSH) to form a disulfide bridge. Cellular antioxidant systems can reduce the disulfide bond and generate the reduced form of the cysteine in proteins. Mutational analysis identified cysteine 330 and 377 of CDC25 phosphatase as the sites for thiol redox reactions; the reduced (-SH) form of CDC25 has phosphatase activity, whereas the oxidized (-S-S-) form is inactive.

FIG. 4.

ROS regulate protein activity. Superoxide dismutase (SOD) converts superoxide (O₂^•−) to hydrogen peroxide (H₂O₂). O₂^•− can modulate the activities of kinases and phosphatases by interacting with metals in one-electron reactions. H₂O₂ can regulate protein function by manipulating thiol-redox reactions in two-electron reactions (36).

FIG. 5.

MnSOD activity protects the chronologic life span of normal human skin fibroblasts. Quiescent normal human skin fibroblasts cultured for 40–60 days at 21% oxygen environment lose their capacity to reenter the proliferative cycle after replating of cells at a lower density. This loss in proliferative capacity is associated with an increase in cellular ROS levels and p16 accumulation. Overexpression of MnSOD suppressed p16 accumulation, increased p21 levels, and protected quiescent fibroblast proliferative capacity (276).

FIG. 6.

Redox control of the cell cycle during wound healing. The wound-healing process can be divided into three stages: inflammation, proliferation, and closure. Higher ROS levels are essential during the inflammatory stage of the wound-healing process to defend against pathogens. Lower levels of ROS later in the wound-healing process could be mitogenic, facilitating quiescent cell entry into the proliferation cycle. Redox control of quiescent cell entry into and exit from the proliferative cycle could be essential to prevent aberrant proliferation and improper closure.

FIG. 7.

Redox control of the cell cycle and lung fibrosis. Elevated levels of nitric oxide (NO) can stimulate proliferation of lung fibroblast by the NF-κB–mediated activation of cyclin D1 expression. NO also is known to decrease p21 and p27 cyclin-dependent kinase inhibitors, which is associated with an increase in cyclin D1/CDK4-6 and cyclin E/CDK2 kinase activities, as well as Rb hyperphosphorylation. Hyperphosphorylated Rb undergoes conformational change releasing the E2F transcription factor. Activation of the E2F-targeted S-phase–specific gene expression prepares cells for DNA synthesis and subsequent cell division.

FIG. 8.

Redox control of the cell cycle and cardiac fibrosis. ROS generated from membrane-bound NADPH oxidase may activate antioxidant enzyme expression that could influence the cellular redox environment in favor of cyclin D and A expression, supporting proliferation. Angiotensin II (Ang II) can induce cardiac fibroblast proliferation and its phenotypic conversion to myofibroblasts, leading to excess collagen and extracellular matrix deposition.

FIG. 9.

Redox control of the cell cycle and liver fibrosis. ROS signaling can recruit quiescent hepatic stellate cells to the proliferative cycle by upregulating the activity of redox-sensitive transcription factors, NF-κB and NRF1. Proliferating hepatic stellate cells can subsequently differentiate into myofibroblasts.

FIG. 10.

Redox control of the cell cycle and cardiovascular diseases. Receptor-mediated ROS signaling can activate cellular proliferation during atherosclerosis. ROS generated from PDGF–ligand interaction can convert PTEN from the reduced form (phosphatase active) to the disulfide form (phosphatase inactive). Inactive PTEN can favor AKT phosphorylation, which in turn can phosphorylate GSK-3β, thereby stabilizing cyclin D1 and facilitating proliferation. ROS signaling can also initiate the ERK pathway, activating growth-promoting transcription factors, c-fos and c-myc. c-fos and c-myc can transcriptionally activate cyclin D1 and cyclin A expression, supporting proliferation. Nitric oxide inhibits proliferation by suppressing cyclin A expression and increasing p21 protein levels.

FIG. 11.

Redox control of the cell cycle and neurodegenerative diseases. ROS signaling can activate growth-promoting signaling pathways facilitating unscheduled entry into the cell cycle. An aborted cell cycle can lead to neuronal cell loss, which is a hallmark of neurodegenerative diseases.

FIG. 12.

Redox control of the cell cycle in human health and disease. A schematic illustration of cell-cycle regulatory processes and redox-gradient is presented. A loss in the redox control of the cell cycle can lead to aberrant proliferation, which is a hallmark of various proliferative disorders. It is hypothesized that reestablishing the redox control of the cell cycle may alleviate many aspects of proliferative disorders.