FIGURE 11.
Targeted degradation of Nrf2 after phosphorylation by PKC. A, MOCK (GFP shRNA control) or Keap1 knockdown Hep3B cells were transfected with empty pcDNA3.1 vector or pcDNA3.1 containing Myc-S40N or Myc-S40D. Forty eight hours after transfection, the cells were grown under normoxia (Nor) or hypoxia (Hyp) for 6 h. Total cell lysates were immunoblotted using anti-c-Myc, anti-Keap1, anti-HIF-1α, or anti-β-actin antibodies. Values are expressed as the mean ± S.D. of three replicates. *, p < 0.05 significantly different from Myc-S40N alone transfected cells; #, p < 0.05 significantly different from Myc-S40D alone transfected cells. B, MOCK (GFP shRNA control) or Siah2 knockdown Hep3B cells were transfected with empty pcDNA3.1 vector or pcDNA3.1 containing Myc-S40N or Myc-S40D. Forty eight hours after transfection, the cells were grown under normoxia or hypoxia for 6 h. Total cell lysates were immunoblotted using anti-c-Myc, anti-HIF-1α, or anti-β-actin antibodies. Values are expressed as the mean ± S.D. of three replicates; *, p < 0.05 significantly different from Myc-S40D alone transfected cells under normoxia; #, p < 0.05 significantly different from Myc-S40D alone transfected cells under hypoxia. C, MOCK (GFP shRNA control) or Keap1 knockdown Hep3B cells were grown under normoxia or hypoxia for 6 h in the presence of DMSO (vehicle control) or calphostin C (0.1 or 0.2 μm). Total cell lysates were immunoblotted with anti-Nrf2, anti-Keap1, anti-HIF-1α or anti-β-actin antibodies. *, p < 0.05; **, p < 0.01 significantly different from untreated MOCK under normoxia; #, p < 0.05 significantly different from untreated Keap1 knockdown cells under hypoxia. D, MOCK (GFP shRNA control) or Siah2 knockdown Hep3B cells were grown under normoxia or hypoxia for 6 h in the presence of DMSO (vehicle control) or calphostin C (0.1 or 0.2 μm). Total cell lysates were immunoblotted with anti-Nrf2, anti-HIF-1α, or anti-β-actin antibodies. **, p < 0.01 significantly different from untreated MOCK under normoxia; ##, p < 0.01 significantly different from untreated MOCK under hypoxia; *, p < 0.05 significantly different from untreated Siah2 knockdown cells under hypoxia.