The Enzyme MnSOD Suppresses Malignant Breast Cell Growth by Preventing HIF-1 Activation
Abstract
Hypoxia inducible factor-1 (HIF-1) is a transcription factor that governs cellular responses to reduced O2 availability by mediating crucial homeostatic processes. The degradation of HIF-1alpha subunit is redox regulated. Manganese superoxide dismutase (MnSOD) is an antioxidant enzyme that can modulate cellular redox environment. Here we show that MnSOD suppresses hypoxic accumulation of HIF-1alpha protein. This suppression can be observed under both 1% O2 and 4% O2. Hypoxic induction of vascular endothelial growth factor (VEGF), a known HIF-1 targeted gene, is also suppressed by elevated MnSOD activity and its expression levels reflected the protein levels of HIF-1alpha. Peroxide removing enzymes located inside the mitochondria (adenoviral GPx-1 and mitochondrial-targeted catalase) inhibited HIF-1alpha protein accumulation in a high MnSOD expressing clone. Increasing peroxisomal/cytosolic catalase activity or inhibition of endogenous catalase by 3-amino-1,2,4-triazole had only a minor effect, suggesting that hydrogen peroxide produced inside mitochondria and not by peroxisomes could mediate the accumulation of HIF-1alpha protein when MnSOD activity is high. These observations demonstrate that HIF-1alpha accumulation is modulated not only by the levels of dioxygen but also the antioxidant enzyme MnSOD.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2005
- Accession Number
- ADA437699
Entities
People
- Garry Buettner
- Min Wang
Organizations
- University of Iowa