Iron metabolism regulates p53 signaling through direct heme-p53 interaction and modulation of p53 localization, stability, and function.
Bottom Line: Iron excess is closely associated with tumorigenesis in multiple types of human cancers, with underlying mechanisms yet unclear.Strikingly, the iron polyporphyrin heme binds to p53 protein, interferes with p53-DNA interactions, and triggers both nuclear export and cytosolic degradation of p53.Moreover, in a tumorigenicity assay, iron deprivation suppressed wild-type p53-dependent tumor growth, suggesting that upregulation of wild-type p53 signaling underlies the selective efficacy of iron deprivation.
Affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.Show MeSH
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Mentions: Mice with homozygous deletion of the human hemochromatosis (Hfe) gene (Hfe−/−) faithfully recapitulate most human HH symptoms, including significant liver iron overload as assessed by Perls’ Prussian Blue staining (Zhou et al., 1998) (Figure 1A). Using a 3,3′,5,5′-tetramethylbenzidine (TMB) assay to quantitatively assess liver heme content, we found that Hfe−/− mouse liver lysate had 9-fold more heme than lysate from wild-type livers (3.71 ± 0.4 nmol/mg protein versus 0.41 ± 0.12 nmol/mg protein) (Figure 1B). We next assessed liver p53 protein content and found that total Hfe−/− liver lysates had significantly lower endogenous p53 protein levels than wild-type livers (Figure 1C). The level of p53 protein in primary hepatocytes from Hfe−/− mice was also markedly lower than that in wild-type hepatocytes (Figure S1A). Moreover, compared to wild-type mice on a normal diet, wild-type mice fed with a high iron diet had considerably lower p53 protein levels (Figures 1D and 1E). Thus, iron overload in mice, due to either a genetic perturbation of iron metabolism or a high iron diet, correlates with a significant reduction in p53 protein levels.
Affiliation: State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China.