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: An examination of the p53 amino acid sequences across several species revealed that all of them bear three putative heme regulatory motifs (HRMs), consisting of Cys-Pro (CP) sequences that occur in a subset of heme-binding proteins (Zhang and Guarente, 1995) (Figures 3A and 3B). A TMB assay verified that the His6-tagged p53 protein, freshly purified from bacteria, contained heme (Figure 3C), whereas a similarly tagged human Ub did not (data not shown). Matrix-assisted laser desorption-ionization (MALDI) mass spectra analysis further confirmed that free heme (m/z 616 ± 2 Da) was associated with freshly purified p53 protein (Figure S2A). In addition, hemin immobilized on agarose beads, but not agarose beads alone, recovered endogenous mouse and human p53 proteins from multiple cell types (Figure S2C). However, p53 protein fractions lost heme during dialysis (Figure S2E), suggesting that heme might associate with p53 non-covalently. p53 proteins, as well as ATE1, bound to heme with a dissociation constant (KD) in the low micromolar range and lost their associated heme at a rate faster than BSA, whose affinity to heme is at nanomolar range (Figure S2E). Under the same conditions, lysozyme, which does not bind to heme, readily lost heme even more quickly (Figure S2E). The rates of heme loss from the heme-binding proteins were thus conversely related to how tightly the proteins might bind to heme.
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.