Manganese superoxide dismutase (Sod2) has emerged as a key enzyme with a dual role in tumorigenic progression. Early studies were primarily directed at defining the tumor suppressive function of Sod2 based on its low level expression in many tumor types. It is now commonly held that loss of Sod2 expression is likely an early event in tumor progression allowing for further propagation of the tumorigenic phenotype resulting from steady state increases in free radical production. Increases in free radical load have also been linked to defects in mitochondrial function and metastatic disease progression. It was initially believed that Sod2 loss may propagate metastatic disease progression, in reality both epidemiologic and experimental evidence indicate that Sod2 levels increase in many tumor types as they progress from early stage non-invasive disease to late stage metastatic disease. Sod2 overexpression in many instances enhances the metastatic phenotype that is reversed by efficient H2O2 scavenging. This review evaluates the many sequelae associated with increases in Sod2 that impinge on the metastatic phenotype. The ability to use Sod2 to modulate the cellular redox-environment has allowed for the identification of redox-responsive signaling events that drive malignancy, such as invasion, migration and prolonged tumor cell survival. Further studies of these redox-driven events will help in the development of targeted therapeutic strategies to efficiently restrict redox-signaling essential for malignant progression.

Baker's yeast, Saccharomyces cerevisiae, can adapt to growth under severe oxygen limitation. Two regulatory systems are described here that control this adaptation. The first involves a heme-dependent repression mechanism. Cells sense hypoxia through the inability to maintain oxygen-dependent heme biosynthesis. Under aerobic conditions, heme accumulates and serves as an effector for the transcriptional activator Hap1. The heme-Hap1 complex activates transcription of the ROX1 gene that encodes a repressor of one set of hypoxic genes. Under hypoxic conditions, heme levels fall, and a heme-deficient Hap1 complex represses ROX1 expression. As a consequence, the hypoxic genes are derepressed. The second regulatory system activates gene expression in response to a variety of stress conditions, including oxygen limitation. Oxygen sensing in this system is heme-independent. The same DNA sequence mediates transcriptional activation of each stress signal.

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Many degenerative disease processes associated with aging result from enhanced extracellular matrix (ECM) breakdown. Concomitant with aberrant matrix destruction are alterations in levels of reactive oxygen species (ROS) generating and detoxification systems. ROS function as second messengers due to their ability to react with wide range of biomolecules resulting in modification of an array of signaling networks. ROS can activate upstream kinases (MKK) responsible for MAPK activation and restrict the activity of their inhibitory phosphatases. Here we focus on the redox-sensitive signaling components that control the expression of MMP-1, which is largely responsible for maintaining ECM homeostasis. Numerous disease processes are associated with shifts in steady-state ROS levels that influence overall ECM degradation. This review highlights the redox-sensitive regulatory signals that control the expression of the primary initiating protease MMP-1 and provides strong rational for the use of antioxidant based therapies for treatment of degenerative disorders associated with aberrant matrix destruction.

Studies from many laboratories have shown that overexpression of manganese superoxide dismutase (MnSOD) inhibits the growth of numerous tumor cell types. The inhibition of tumor cell growth can be attributed to the increase in the steady-state levels of H2O2 as a result of the increased dismuting activity of MnSOD. Here we demonstrate that overexpression of MnSOD enhances the activity of the superoxide (O2*-)-sensitive enzyme aconitase, decreases the intracellular GSH/GSSG ratio, and dose-dependently inhibits pyruvate carboxylase activity. Thus, alterations in the steady-state concentrations of mitochondrial O2*- and H2O2 as a result of MnSOD overexpression can alter the metabolic capacity of the cell leading to inhibition of cell growth. Furthermore, we propose that MnSOD overexpression can modulate the activity of nitric oxide (*NO) by preventing its reaction with O2*-. This hypothesis suggests that the redox environment of the mitochondria can be altered to favor the activity of *NO rather than peroxynitrite (ONOO-) and may explain the enhanced toxicity of *NO-generating compounds toward MnSOD-overexpressing cell lines. These findings indicate that therapeutic strategies targeted at overexpressing MnSOD in tumor tissue may be more effective when used in combination with agents that deplete the oxidant-buffering and enhance the *NO-generating capacity of the tumor and host, respectively.