No abstract

Reactive oxygen species (ROS), 1 which are detrimental to cellular structures and activities, are generated during the course of normal cellular metabolism and in response to noxious, exogenous stimuli such as heavy metals, UV irradiation, and bacterial toxins. Cells utilize both exogenous (e.g. vitamins and plant-derived phenolic antioxidants) and endogenous (e.g. catalase and superoxide dismutase) mechanisms to detoxify ROS. A continuing imbalance between ROS production and ROS detoxification, however, results in cellular oxidative stress. In an effort to maintain cellular homeostasis, cells respond to this imbalance in part by modulating the expression of a select set of genes that encode proteins with antioxidant and cytoprotective activities. Central to this response are the transcription factors that control the activation of these stressresponsive genes. Examples of such stress-responsive transcription factors include the well-characterized heat shock factors (1) and members of the AP-1 (2, 3) and NF-B (3) families of proteins.Recent studies from several laboratories have identified another potentially important stress-responsive transcription factor, Nrf2. Like the AP-1 constituents, Fos and Jun factors, Nrf2 is a basic-leucine zipper (bZIP) protein that functions as an obligate dimer (4, 5

No abstract

MCL-1, an anti-apoptotic BCL-2 family member that is essential for the survival of multiple cell lineages, is also among the most highly amplified genes in cancer. Although MCL-1 is known to oppose cell death, precisely how it functions to promote survival of normal and malignant cells is poorly understood. Here, we report that different forms of MCL-1 reside in distinct mitochondrial locations and exhibit separable functions. On the outer mitochondrial membrane, a MCL-1 isoform acts like other anti-apoptotic BCL-2 molecules to antagonize apoptosis, whereas an amino-terminally truncated isoform of MCL-1 that is imported into the mitochondrial matrix is necessary to facilitate normal mitochondrial fusion, ATP production, membrane potential, respiration, cristae ultrastructure, and maintenance of oligomeric ATP synthase. Our results provide insight into how MCL-1's surprisingly diverse salutary functions may control the survival of both normal and cancer cells.