The heme-p53 interaction: Linking iron metabolism to p53 signaling and tumorigenesis.
Ontology highlight
ABSTRACT:
SUBMITTER: Shen J
PROVIDER: S-EPMC4845248 | biostudies-other | 2016 Jan
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Iron excess is closely associated with tumorigenesis in multiple types of human cancers, with underlying mechanisms yet unclear. Recently, iron deprivation has emerged as a major strategy for chemotherapy, but it exerts tumor suppression only on select human malignancies. Here, we report that the tumor suppressor protein p53 is downregulated during iron excess. 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. Our findings thus identify a direct link between iron/heme homeostasis and the regulation of p53 signaling, which not only provides mechanistic insights into iron-excess-associated tumorigenesis but may also help predict and improve outcomes in iron-deprivation-based chemotherapy.
| S-EPMC4219651 | biostudies-literature
Project description:p53 is a hallmark tumor suppressor due in part to its role in cell cycle progression, DNA damage repair, and cellular apoptosis; its protein activity interrelates with the Sirtuin family of proteins, major regulators of the cellular response to metabolic, oxidative, and genotoxic stress. In the recent years, mammalian Sirtuin 7 (SIRT7) has emerged as a pivotal regulator of p53, fine-tuning its activity in a context dependent manner. SIRT7 is frequently overexpressed in human cancer, yet its precise role in tumorigenesis and whether it involves p53 regulation is insufficiently understood. Depletion of SIRT7 in mice results in impaired embryo development and premature aging. While p53 activity has been suggested to contribute to tissue specific dysfunction in adult Sirt7 -/- mice, whether this also applies during development is currently unknown. By generating SIRT7 and p53 double-knockout mice, here we show that the demise of SIRT7-deficient embryos is not the result of p53 activity. Notably, although SIRT7 is commonly considered an oncogene, SIRT7 haploinsufficiency increases tumorigenesis in p53 knockout mice. Remarkably, in specific human tumors harboring p53 mutation, we identified that SIRT7 low expression correlates with poor patient prognosis. Transcriptomic analysis unveils a previously unrecognized interplay between SIRT7 and p53 in epithelial-to-mesenchymal transition (EMT) and extracellular matrix regulation with major implications for our understanding of embryonic development and tumor progression.
| S-EPMC10791984 | biostudies-literature
Project description:The circadian rhythm of the liver maintains glucose homeostasis, and disruption of this rhythm is associated with type 2 diabetes. Feeding is one factor that sets the circadian clock in peripheral tissues, but relatively little is known about the role of specific dietary components in that regard. We assessed the effects of dietary iron on circadian gluconeogenesis. Dietary iron affects circadian glucose metabolism through heme-mediated regulation of the interaction of nuclear receptor subfamily 1 group d member 1 (Rev-Erbα) with its cosuppressor nuclear receptor corepressor 1 (NCOR). Loss of regulated heme synthesis was achieved by aminolevulinic acid (ALA) treatment of mice or cultured cells to bypass the rate-limiting enzyme in hepatic heme synthesis, ALA synthase 1 (ALAS1). ALA treatment abolishes differences in hepatic glucose production and in the expression of gluconeogenic enzymes seen with variation of dietary iron. The differences among diets are also lost with inhibition of heme synthesis with isonicotinylhydrazine. Dietary iron modulates levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a transcriptional activator of ALAS1, to affect hepatic heme. Treatment of mice with the antioxidant N-acetylcysteine diminishes PGC-1α variation observed among the iron diets, suggesting that iron is acting through reactive oxygen species signaling.
| S-EPMC4375081 | biostudies-literature
Project description:Mutant p53 (mtp53) proteins can exert cancer-promoting gain-of-function activities. We report a mechanism by which mtp53 suppresses both cell-autonomous and non-cell-autonomous signaling to promote cancer cell survival and evasion of tumor immune surveillance. Mtp53 interferes with the function of the cytoplasmic DNA sensing machinery, cGAS-STING-TBK1-IRF3, that activates the innate immune response. Mtp53, but not wild-type p53, binds to TANK-binding protein kinase 1 (TBK1) and prevents the formation of a trimeric complex between TBK1, STING, and IRF3, which is required for activation, nuclear translocation, and transcriptional activity of IRF3. Inactivation of innate immune signaling by mtp53 alters cytokine production, resulting in immune evasion. Restoring TBK1 signaling is sufficient to bypass mtp53 and lead to restored immune cell function and cancer cell eradication. This work is of translational interest because therapeutic approaches that restore TBK1 function could potentially reactivate immune surveillance and eliminate mtp53 tumors.
| S-EPMC8044023 | biostudies-literature
Project description:p53 is known to play a role in iron homeostasis and is required for FDXR-mediated iron metabolism via iron regulatory protein 2 (IRP2). Interestingly, p53 is frequently mutated in tumors wherein iron is often accumulated, suggesting that mutant p53 may exert its gain of function by altering iron metabolism. In this study, we found that FDXR deficiency decreased mutant p53 expression along with altered iron metabolism in p53R270H/- MEFs and cancer cells carrying mutant p53. Consistently, we found that decreased expression of mutant p53 by FDXR deficiency inhibited mutant p53-R270H to induce carcinoma and high grade pleomorphic sarcoma in FDXR+/-; p53R270H/- mice as compared with p53R270H/- mice. Moreover, we found that like its effect on wild-type p53, loss of IRP2 increased mutant p53 expression. However, unlike its effect to suppress cell growth in cells carrying wild-type p53, loss of IRP2 promoted cell growth in cancer cells expressing mutant p53. Finally, we found that ectopic expression of IRP2 suppressed cell growth in a mutant p53-dependent manner. Together, our data indicate that mutant p53 gain-of-function can be suppressed by IRP2 and FDXR deficiency, both of which may be explored to target tumors carrying mutant p53.
| S-EPMC7122131 | biostudies-literature
Project description:Thrombosis is one of the leading causes of death worldwide. As such, it also occurs as one of the major complications in hemolytic diseases, like hemolytic uremic syndrome, hemorrhage and sickle cell disease. Under these conditions, red blood cell lysis finally leads to the release of large amounts of labile heme into the vascular compartment. This, in turn, can trigger oxidative stress and proinflammatory reactions. Moreover, the heme-induced activation of the blood coagulation system was suggested as a mechanism for the initiation of thrombotic events under hemolytic conditions. Studies of heme infusion and subsequent thrombotic reactions support this assumption. Furthermore, several direct effects of heme on different cellular and protein components of the blood coagulation system were reported. However, these effects are controversially discussed or not yet fully understood. This review summarizes the existing reports on heme and its interference in coagulation processes, emphasizing the relevance of considering heme in the context of the treatment of thrombosis in patients with hemolytic disorders.
| S-EPMC7865584 | biostudies-literature
Project description:The hexosamine biosynthetic pathway (HBP) is highly dependent on multiple metabolic nutrients including glucose, glutamine, and acetyl-CoA. Increased flux through HBP leads to elevated post-translational addition of β-D-N-acetylglucosamine sugars to nuclear and cytoplasmic proteins. Increased total O-GlcNAcylation is emerging as a general characteristic of cancer cells, and recent studies suggest that O-GlcNAcylation is a central communicator of nutritional status to control key signaling and metabolic pathways that regulate multiple cancer cell phenotypes. This review summarizes our current understanding of changes of O-GlcNAc cycling enzymes in cancer, the role of O-GlcNAcylation in tumorigenesis, and the current challenges in targeting this pathway therapeutically.
| S-EPMC4983259 | biostudies-other
Project description:BackgroundSenescent red blood cells (RBC) are recognized, phagocytosed and cleared by tissue macrophages. During this erythrophagocytosis (EP), RBC are engulfed and processed in special compartments called erythrophagosomes. We previously described that following EP, heme is rapidly degraded through the catabolic activity of heme oxygenase (HO). Extracted heme iron is then either exported or stored by macrophages. However, the cellular localization of the early steps of heme processing and iron extraction during EP remains to be clearly defined.Methodology/principal findingsWe took advantage of our previously described cellular model of EP, using bone marrow-derived macrophages (BMDM). The subcellular localization of both inducible and constitutive isoforms of HO (HO-1 and HO-2), of the divalent metal transporters (Nramp1, Nramp2/DMT1, Fpn), and of the recently identified heme transporter HRG-1, was followed by fluorescence and electron microscopy during the earliest steps of EP. We also looked at some ER [calnexin, glucose-6-phosphatase (G6Pase) activity] and lysosomes (Lamp1) markers during EP. In both quiescent and LPS-activated BMDM, Nramp1 and Lamp1 were shown to be strong markers of the erythrophagolysosomal membrane. HRG-1 was also recruited to the erythrophagosome. Furthermore, we observed calnexin labeling and G6Pase activity at the erythrophagosomal membrane, indicating the contribution of ER in this phagocytosis model. In contrast, Nramp2/DMT1, Fpn, HO-1 and HO-2 were not detected at the membrane of erythrophagosomes.Conclusions/significanceOur study highlights the subcellular localization of various heme- and iron-related proteins during early steps of EP, thereby suggesting a model for heme catabolism occurring outside the phagosome, with heme likely being transported into the cytosol through HRG1. The precise function of Nramp1 at the phagosomal membrane in this model remains to be determined.
| S-EPMC3408460 | biostudies-literature
Project description:Rnf8 is an E3 ubiquitin ligase that plays a key role in the DNA damage response as well as in the maintenance of telomeres and chromatin remodeling. Rnf8(-/-) mice exhibit developmental defects and increased susceptibility to tumorigenesis. We observed that levels of p53, a central regulator of the cellular response to DNA damage, increased in Rnf8(-/-) mice in a tissue- and cell type-specific manner. To investigate the role of the p53-pathway inactivation on the phenotype observed in Rnf8(-/-) mice, we have generated Rnf8(-/-)p53(-/-) mice. Double-knockout mice showed similar growth retardation defects and impaired class switch recombination compared to Rnf8(-/-) mice. In contrast, loss of p53 fully rescued the increased apoptosis and reduced number of thymocytes and splenocytes in Rnf8(-/-) mice. Similarly, the senescence phenotype of Rnf8(-/-) mouse embryonic fibroblasts was rescued in p53 null background. Rnf8(-/-)p53(-/-) cells displayed defective cell cycle checkpoints and DNA double-strand break repair. In addition, Rnf8(-/-)p53(-/-) mice had increased levels of genomic instability and a remarkably elevated tumor incidence compared to either Rnf8(-/-) or p53(-/-) mice. Altogether, the data in this study highlight the importance of p53-pathway activation upon loss of Rnf8, suggesting that Rnf8 and p53 functionally interact to protect against genomic instability and tumorigenesis.
| S-EPMC3561120 | biostudies-literature
Project description:Sideroflexin4 (SFXN4) is a member of a family of nuclear-encoded mitochondrial proteins. Rare germline mutations in SFXN4 lead to phenotypic characteristics of mitochondrial disease including impaired mitochondrial respiration and hematopoetic abnormalities. We sought to explore the function of this protein. We show that knockout of SFXN4 has profound effects on Fe-S cluster formation. This in turn diminishes mitochondrial respiratory chain complexes and mitochondrial respiration and causes a shift to glycolytic metabolism. SFXN4 knockdown reduces the stability and activity of cellular Fe-S proteins, affects iron metabolism by influencing the cytosolic aconitase-IRP1 switch, redistributes iron from the cytosol to mitochondria, and impacts heme synthesis by reducing levels of ferrochelatase and inhibiting translation of ALAS2. We conclude that SFXN4 is essential for normal functioning of mitochondria, is necessary for Fe-S cluster biogenesis and iron homeostasis, and plays a critical role in mitochondrial respiration and synthesis of heme.
| S-EPMC6928202 | biostudies-literature