K. Maehara et al., Early growth responsive-1-dependent manganese superoxide dismutase gene transcription mediated by platelet-derived growth factor, FASEB J, 15(9), 2001, pp. NIL_209-NIL_233
Manganese superoxide dismutase (Mn-SOD) plays a major role in protecting mi
tochondria from oxidative damage. Overexpression of Mn-SOD maintains cell s
urvival under conditions that lead to apoptotic death. In addition to the a
ntioxidative enzyme, platelet-derived growth factor (PDGF) is a principal s
urvival factor that inhibits apoptosis and promotes proliferation by activa
ting survival signaling pathways in various cells. Here we show that PDGF i
nduced the expression of the Mn-SOD gene in NIH3T3 cells, and its induction
was associated with early growth response-1 (Egr-1), a transcription facto
r. 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 ma
nner. The pathway by which PDGF induced Egr-1 involved the mitogen-activate
d 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 b
y PDGF.