Early growth responsive‐1‐dependent manganese superoxide dismutase gene transcription mediated by platelet‐derived growth factor

Manganese superoxide dismutase (Mn‐SOD) plays a major role in protecting mitochondria from oxidative damage. Overexpression of Mn‐SOD maintains cell survival under conditions that lead to apoptotic death. In addition to the antioxidative enzyme, platelet‐derived growth factor (PDGF) is a principal survival factor that inhibits apoptosis and promotes proliferation by activating survival signaling pathways in various cells. Here we show that PDGF induced the expression of the Mn‐SOD gene in NIH3T3 cells, and its induction was associated with early growth response‐1 (Egr‐1), a transcription factor. An electrophoretic mobility shift assay demonstrated that Egr‐1 bound to the proximal promoter of the Mn‐SOD gene in response to PDGF. The proximal promoter region of Mn‐SOD was shown to be transcriptionally responsive to both basal and PDGF stimulation by transfection studies. Forced expression of Egr‐1 in the cells activated Mn‐SOD transcription in a dose‐dependent manner. The pathway by which PDGF induced Egr‐1 involved the mitogen‐activated protein kinase kinase‐1 (MEK1) and extracellular signal‐regulated kinases 1 and 2 (ERK1/2), because the effect of PDGF on the induction of Egr‐1 was blocked by U0126, a specific MEK1 inhibitor. These findings indicate that the induction of Mn‐SOD is part of the anti‐apoptotic properties mediated by PDGF.