FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression

We have shown previously that FOXO3a induces the expression of c-Myc antagonists of the Mad/Mxd family

E C Ferber; B Peck; O Delpuech; G P Bell; P East; A Schulze

2011

Scholarcy highlights

  • The mitochondrial genome encodes only 13 proteins
  • As loss of c-Myc protein following FOXO3a activation was not associated with a significant reduction in c-Myc mRNA levels, we examined the effect of FOXO3a activation on c-Myc protein stability. c-Myc is regulated by phosphorylation-dependent ubiquitination and proteasomal degradation
  • We found that downregulation of mitochondrial gene expression by FOXO3a was mediated through c-Myc inhibition. c-Myc has a well-established role in regulating mitochondrial gene expression
  • We found that the reduction in reactive oxygen species levels by FOXO3a activation was independent of SOD2 but was reversed by reexpression of c-Myc
  • Previous studies showed that FOXO3a is induced in hypoxia and can inhibit HIF1-a-dependent gene expression by directly binding to HIF-1a37 or through induction of the transcriptional cofactor CITED2.25 studies in neural stem cells from foxo3aÀ/À mice revealed that FOXO3a is required for the expression of hypoxia-dependent genes
  • DL2312 and parental DLD-1 cells were grown in RPMI 1640 supplemented with 10% fetal calf serum. 4-OHT was dissolved in ethanol and used at a final concentration of 100 nM
  • FOXO3a activation prevented hypoxic accumulation of hypoxia-inducible factor-1a, which was restored by re-expression of c-Myc. Previous studies showed that FOXO3a is induced in hypoxia and can inhibit HIF1-a-dependent gene expression by directly binding to HIF-1a37 or through induction of the transcriptional cofactor CITED2.25 studies in neural stem cells from foxo3aÀ/À mice revealed that FOXO3a is required for the expression of hypoxia-dependent genes. Decreasing mitochondrial function is an important role of HIF-1a in the response to hypoxia

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