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Iron regulatory protein 2 is a suppressor of mutant p53 in tumorigenesis

Oncogene volume 38, pages 6256–6269 (2019)Cite this article

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Abstract

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.

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The authors declare that all data supporting the findings of this study are available within the article and its supplementary information files.

References

  1. Freed-Pastor WA, Prives C. Mutantp53: one name, many proteins. Genes Dev. 2012;26:1268–86.

    Article  CAS  Google Scholar 

  2. Muller PA, Vousden KH. p53 mutations in cancer. Nat Cell Biol. 2013;15:2–8.

    Article  CAS  Google Scholar 

  3. Oren M, Rotter V. Mutant p53 gain-of-function in cancer. Cold Spring Harb Perspect Biol. 2010;2:a001107.

    Article  Google Scholar 

  4. Hanel W, Marchenko N, Xu S, Yu SX, Weng W, Moll U. Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis. Cell Death Differ. 2013;20:898–909.

    Article  CAS  Google Scholar 

  5. Lang GA, Iwakuma T, Suh YA, Liu G, Rao VA, Parant JM, et al. Gain of function of a p53 hot spot mutation in a mouse model of Li–Fraumeni syndrome. Cell. 2004;119:861–72.

    Article  CAS  Google Scholar 

  6. Lee MK, Teoh WW, Phang BH, Tong WM, Wang ZQ, Sabapathy K. Cell-type, dose, and mutation-type specificity dictate mutant p53 functions in vivo. Cancer Cell. 2012;22:751–64.

    Article  CAS  Google Scholar 

  7. Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT, et al. Mutant p53 gain of function in two mouse models of Li–Fraumeni syndrome. Cell. 2004;119:847–60.

    Article  CAS  Google Scholar 

  8. Zhou G, Wang J, Zhao M, Xie TX, Tanaka N, Sano D, et al. Gain-of-function mutant p53 promotes cell growth and cancer cell metabolism via inhibition of AMPK activation. Mol Cell. 2014;54:960–74.

    Article  CAS  Google Scholar 

  9. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell. 2010;142:24–38.

    Article  CAS  Google Scholar 

  10. Lawen A, Lane DJ. Mammalian iron homeostasis in health and disease: uptake, storage, transport, and molecular mechanisms of action. Antioxid Redox Signal. 2013;18:2473–507.

    Article  CAS  Google Scholar 

  11. Wang J, Pantopoulos K. Regulation of cellular iron metabolism. Biochem J. 2011;434:365–81.

    Article  CAS  Google Scholar 

  12. Torti SV, Torti FM. Iron and cancer: more ore to be mined. Nat Rev Cancer. 2013;13:342–55.

    Article  CAS  Google Scholar 

  13. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  Google Scholar 

  14. Fonseca-Nunes A, Jakszyn P, Agudo A. Iron and cancer risk-a systematic review and meta-analysis of the epidemiological evidence. Cancer Epidemiol Biomark Prev. 2014;23:12–31.

    Article  CAS  Google Scholar 

  15. Kwok JC, Richardson DR. The iron metabolism of neoplastic cells: alterations that facilitate proliferation? Crit Rev Oncol/Hematol. 2002;42:65–78.

    Article  Google Scholar 

  16. Beutler E. Hemochromatosis: genetics and pathophysiology. Annu Rev Med. 2006;57:331–47.

    Article  CAS  Google Scholar 

  17. Hann HW, Stahlhut MW, Hann CL. Effect of iron and desferoxamine on cell growth and in vitro ferritin synthesis in human hepatoma cell lines. Hepatology. 1990;11:566–9.

    Article  CAS  Google Scholar 

  18. Shaheen NJ, Silverman LM, Keku T, Lawrence LB, Rohlfs EM, Martin CF, et al. Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer. J Natl Cancer Inst. 2003;95:154–9.

    Article  CAS  Google Scholar 

  19. Simcox JA, McClain DA. Iron and diabetes risk. Cell Metab. 2013;17:329–41.

    Article  CAS  Google Scholar 

  20. Smith AG, Carthew P, Clothier B, Constantin D, Francis JE, Madra S. Synergy of iron in the toxicity and carcinogenicity of polychlorinated biphenyls (PCBs) and related chemicals. Toxicol Lett. 1995;82-83:945–50.

    Article  CAS  Google Scholar 

  21. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090–3.

    Article  CAS  Google Scholar 

  22. Hentze MW, Seuanez HN, O’Brien SJ, Harford JB, Klausner RD. Chromosomal localization of nucleic acid-binding proteins by affinity mapping: assignment of the IRE-binding protein gene to human chromosome 9. Nucleic Acids Res. 1989;17:6103–8.

    Article  CAS  Google Scholar 

  23. Rouault TA, Tang CK, Kaptain S, Burgess WH, Haile DJ, Samaniego F, et al. Cloning of the cDNA encoding an RNA regulatory protein-the human iron-responsive element-binding protein. Proc Natl Acad Sci USA. 1990;87:7958–62.

    Article  CAS  Google Scholar 

  24. Butt J, Kim HY, Basilion JP, Cohen S, Iwai K, Philpott CC, et al. Differences in the RNA binding sites of iron regulatory proteins and potential target diversity. Proc Natl Acad Sci USA. 1996;93:4345–9.

    Article  CAS  Google Scholar 

  25. Henderson BR, Menotti E, Kuhn LC. Iron regulatory proteins 1 and 2 bind distinct sets of RNA target sequences. J Biol Chem. 1996;271:4900–8.

    Article  CAS  Google Scholar 

  26. Rouault TA. The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol. 2006;2:406–14.

    Article  CAS  Google Scholar 

  27. Zhang F, Wang W, Tsuji Y, Torti SV, Torti FM. Post-transcriptional modulation of iron homeostasis during p53-dependent growth arrest. J Biol Chem. 2008;283:33911–8.

    Article  CAS  Google Scholar 

  28. Gunshin H, Allerson CR, Polycarpou-Schwarz M, Rofts A, Rogers JT, Kishi F, et al. Iron-dependent regulation of the divalent metal ion transporter. FEBS Letters. 2001;509:309–16.

    Article  CAS  Google Scholar 

  29. Brandt ME, Vickery LE. Expression and characterization of human mitochondrial ferredoxin reductase in Escherichia coli. Arch Biochem Biophys. 1992;294:735–40.

    Article  CAS  Google Scholar 

  30. Lange H, Kaut A, Kispal G, Lill R. A mitochondrial ferredoxin is essential for biogenesis of cellular iron-sulfur proteins. Proc Natl Acad Sci USA. 2000;97:1050–5.

    Article  CAS  Google Scholar 

  31. Muller JJ, Lapko A, Bourenkov G, Ruckpaul K, Heinemann U. Adrenodoxin reductase-adrenodoxin complex structure suggests electron transfer path in steroid biosynthesis. J Biol Chem. 2001;276:2786–9.

    Article  CAS  Google Scholar 

  32. Sheftel AD, Stehling O, Pierik AJ, Elsasser HP, Muhlenhoff U, Webert H, et al. Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis. Proc Natl Acad Sci USA. 2010;107:11775–80.

    Article  CAS  Google Scholar 

  33. Shi Y, Ghosh M, Kovtunovych G, Crooks DR, Rouault TA. Both human ferredoxins 1 and 2 and ferredoxin reductase are important for iron-sulfur cluster biogenesis. Biochim Biophys Acta. 2012;1823:484–92.

    Article  CAS  Google Scholar 

  34. Hwang PM, Bunz F, Yu J, Rago C, Chan TA, Murphy MP, et al. Ferredoxin reductase affects p53-dependent, 5-fluorouracil-induced apoptosis in colorectal cancer cells. Nat Med. 2001;7:1111–7.

    Article  CAS  Google Scholar 

  35. Liu G, Chen X. The ferredoxin reductase gene is regulated by the p53 family and sensitizes cells to oxidative stress-induced apoptosis. Oncogene. 2002;21:7195–204.

    Article  CAS  Google Scholar 

  36. Edmondson DA, Karski EE, Kohlgruber A, Koneru H, Matthay KK, Allen S, et al. Transcript analysis for internal biodosimetry using peripheral blood from neuroblastoma patients treated with (131)I-mIBG, a targeted radionuclide. Radiat Res. 2016;186:235–44.

    Article  CAS  Google Scholar 

  37. Lacombe J, Sima C, Amundson SA, Zenhausern F. Candidate gene biodosimetry markers of exposure to external ionizing radiation in human blood: a systematic review. PLoS ONE. 2018;13:e0198851.

    Article  Google Scholar 

  38. O’Brien G, Cruz-Garcia L, Majewski M, Grepl J, Abend M, Port M, et al. FDXR is a biomarker of radiation exposure in vivo. Sci Rep. 2018;8:684.

    Article  Google Scholar 

  39. Okumura H, Uchikado Y, Omoto I, Motomura M, Kita Y, Sasaki K, et al. Ferredoxin reductase is useful for predicting the effect of chemoradiation therapy on esophageal squamous cell carcinoma. Anticancer Res. 2015;35:6471–4.

    CAS  PubMed  Google Scholar 

  40. Yu J, Marsh S, Ahluwalia R, McLeod HL. Ferredoxin reductase: pharmacogenomic assessment in colorectal cancer. Cancer Res. 2003;63:6170–3.

    CAS  PubMed  Google Scholar 

  41. Zhang Y, Qian Y, Zhang J, Yan W, Jung YS, Chen M, et al. Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2. Genes Dev. 2017;31:1243–56.

    Article  CAS  Google Scholar 

  42. Elbendary AA, Cirisano FD, Evans AC Jr, Davis PL, Iglehart JD, Marks JR, et al. Relationship between p21 expression and mutation of the p53 tumor suppressor gene in normal and malignant ovarian epithelial cells. Clin Cancer Res. 1996;2:1571–5.

    CAS  PubMed  Google Scholar 

  43. Sauer L, Gitenay D, Vo C, Baron VT. Mutant p53 initiates a feedback loop that involves Egr-1/EGF receptor/ERK in prostate cancer cells. Oncogene. 2010;29:2628–37.

    Article  CAS  Google Scholar 

  44. Yang HJ, Zhang J, Yan W, Cho SJ, Lucchesi C, Chen M, et al. Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner. Proc Natl Acad Sci USA. 2017;114:11500–5.

    Article  CAS  Google Scholar 

  45. Yan W, Chen X. Characterization of functional domains necessary for mutant p53 gain of function. J Biol Chem. 2010;285:14229–38.

    Article  CAS  Google Scholar 

  46. Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57–62.

    Article  CAS  Google Scholar 

  47. Bertout JA, Patel SA, Fryer BH, Durham AC, Covello KL, Olive KP, et al. Heterozygosity for hypoxia inducible factor 1alpha decreases the incidence of thymic lymphomas in a p53 mutant mouse model. Cancer Res. 2009;69:3213–20.

    Article  CAS  Google Scholar 

  48. Zhang J, Wang C, Chen X, Takada M, Fan C, Zheng X, et al. EglN2 associates with the NRF1-PGC1alpha complex and controls mitochondrial function in breast cancer. EMBO J. 2015;34:2953–70.

    Article  Google Scholar 

  49. Hershko C, Link G, Pinson A, Peter HH, Dobbin P, Hider RC. Iron mobilization from myocardial cells by 3-hydroxypyridin-4-one chelators: studies in rat heart cells in culture. Blood. 1991;77:2049–53.

    CAS  PubMed  Google Scholar 

  50. Porter JB, Abeysinghe RD, Marshall L, Hider RC, Singh S. Kinetics of removal and reappearance of non-transferrin-bound plasma iron with deferoxamine therapy. Blood. 1996;88:705–13.

    CAS  PubMed  Google Scholar 

  51. Xie Y, Zhu S, Song X, Sun X, Fan Y, Liu J, et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep. 2017;20:1692–704.

    Article  CAS  Google Scholar 

  52. Zhang J, Xu E, Ren C, Yang HJ, Zhang Y, Sun W, et al. Genetic ablation of Rbm38 promotes lymphomagenesis in the context of mutant p53 by downregulating PTEN. Cancer Res. 2018;78:1511–21.

    Article  CAS  Google Scholar 

  53. Guo B, Yu Y, Leibold EA. Iron regulates cytoplasmic levels of a novel iron-responsive element-binding protein without aconitase activity. J Biol Chem. 1994;269:24252–60.

    CAS  PubMed  Google Scholar 

  54. Guzman C, Bagga M, Kaur A, Westermarck J, Abankwa D. ColonyArea: an ImageJ plugin to automatically quantify colony formation in clonogenic assays. PLoS ONE. 2014;9:e92444.

    Article  Google Scholar 

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Acknowledgements

This work was supported in part by the National Institutes of Health grants CA224433-01. The authors would like to thank Dr. Elizabeth Leibold and Dr. Kuanyu Li for their generous gifts of IRP2 antibodies.

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Authors and Affiliations

  1. Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California at Davis, Davis, CA, 95616, USA

    Yanhong Zhang, Xiuli Feng, Jin Zhang & Xinbin Chen

  2. College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, China

    Xiuli Feng

  3. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Minyi Chen

  4. Department of Pathology, University of Washington, Seattle, WA, 98104, USA

    Eric Huang

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Zhang, Y., Feng, X., Zhang, J. et al. Iron regulatory protein 2 is a suppressor of mutant p53 in tumorigenesis. Oncogene 38, 6256–6269 (2019). https://doi.org/10.1038/s41388-019-0876-5

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