Nuclear SOD1 in Growth Control, Oxidative Stress Response, Amyotrophic Lateral Sclerosis, and Cancer

Abstract

SOD1 is the major superoxide dismutase responsible for catalyzing dismutation of superoxide to hydrogen peroxide and molecular oxygen. It is well known as an essential antioxidant enzyme for maintaining cellular redox homeostasis. SOD1 dysregulation has been associated with many diseases, including amyotrophic lateral sclerosis (ALS), cancer, accelerated aging, and age-related diseases. Recent studies also revealed that SOD1 can serve as a regulatory protein in cell signaling, transcription, and ribosome biogenesis. Notably, SOD1 is localized in the nucleus under both normal and pathological conditions, contributing to oxidative stress response and growth control. Moreover, increasing evidence points to the importance of nuclear SOD1 in the pathogenesis of ALS and cancer.

Keywords: amyotrophic lateral sclerosis (ALS); cancer; cell signaling; reactive oxidative species (ROS); ribosome biogenesis; superoxide dismutase 1 (SOD1); transcription.

Figure 1

SOD1 is a transcription factor that regulates of redox homeostasis. Upon activation by H₂O_2, ATM-CHK2-dependent phosphorylation promotes accumulation of SOD1 in the nucleus, where SOD1 binds to promoters and regulates expression of genes involved in oxidative stress responses. SBM, SOD1 binding motif.

Figure 2

Roles of nuclear SOD1 in cancer. Nuclear SOD1 contributes to growth of cancer cells by at least three distinct mechanisms. First, SOD1 acts as a transcription factor that promotes expression of genes that mitigate oxidative stress in cancer cells. Second, SOD1 binds to gene promoters and regulates expression of multiple oncogenes and tumor suppressor genes. Third, SOD1 is partially localized in the nucleolus and regulates assembly of the PeBoW complex, which stimulates pre-rRNA processing and ribosome biogenesis. SBM, SOD1 binding motif.

Figure 3

Role of nuclear SOD1 in ALS. Misfolding and aggregation of SOD1 may cause motor neuron cytotoxicity by interfering with nuclear SOD1 localization and function. SOD1 aggregates in the cytoplasm appear to block ATM/CHK2-stimulated nuclear localization and transcriptional activity of SOD1, which is required for oxidative stress resistance and neuroprotection. SOD1 aggregates also occur in the nucleus where they disrupt the SMN complex, contributing to ALS disease progression. CRM1-mediated export of unfolded SOD1 from the nucleus may help alleviate the neurotoxic effects of SOD1 aggregates. SBM, SOD1 binding motif.