Extracellular Superoxide Dismutase: Growth Promoter or Tumor Suppressor?

Figure 1

Suggested positive feedback loop in SOD3 signal transduction. Phosphorylation of RTKs activates the cell membrane associated SRC proto-oncogene family members that contribute to RAS GTP loading and stimulation of mitogenic signal transduction to BRAF, MEK1/2, and ERK1/2 kinases. In vitro transient transfection of RAS, BRAF, MEK1/2, and ERK1/2 increases both SOD3 mRNA and protein expression hence suggesting mitogen pathway induced SOD3 synthesis. SOD3 production results in increased synthesis of growth promoters, such as VEGF and cyclin D1, and increased activation of activator protein 1 (AP1) and cAMP response element-binding protein (CREB). Importantly, SOD3 activates cell surface receptor tyrosine kinases (RTKs), increases phosphorylation of SRC family members, and regulates the GTP loading to small GTPases, such as RAS.