Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to proliferative Ras/RAF and nutrient-dependent mTOR signaling

Blood

Volumn 123, Issue 10, 2014, Pages 1574-1585

  Mleczko Sanecka, Katarzyna ^a,b   Roche, Franziska ^a   Da Silva, Ana Rita ^a,b   Call, Debora ^a   D'Alessio, Flavia ^a,b   Ragab, Anan ^a   Lapinski, Philip E ^c   Ummanni, Ramesh ^d   Korf, Ulrike ^d   Oakes, Christopher ^d   Damm, Georg ^e   D'Alessandro, Lorenza A ^d   Klingmüller, Ursula ^d   King, Philip D ^c   Boutros, Michael ^a   Hentze, Matthias W ^a,b   Muckenthaler, Martina U ^a  

^a UNIVERSITY OF HEIDELBERG   (Germany)

^b EUROPEAN MOLECULAR BIOLOGY LABORATORY   (Germany)

^c UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

^d GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

^e CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

HEPCIDIN; INTERLEUKIN 6; IRON; MAMMALIAN TARGET OF RAPAMYCIN; MITOGENIC AGENT; RAF PROTEIN; RAS PROTEIN;

ANIMAL EXPERIMENT; ARTICLE; CELL GROWTH; CELL PROLIFERATION; CONTROLLED STUDY; GENETIC ASSOCIATION; GENETIC TRANSCRIPTION; HOMEOSTASIS; HUMAN; HUMAN CELL; INFLAMMATION; LIVER CELL CARCINOMA; MALE; MOUSE; NONHUMAN; NUTRIENT; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN MICROARRAY; RNA INTERFERENCE; SIGNAL TRANSDUCTION; STEADY STATE;

ANIMALS; BONE MORPHOGENETIC PROTEINS; CELL LINE; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; HEPCIDINS; HUMANS; MALE; MICE; MICE, KNOCKOUT; MITOGEN-ACTIVATED PROTEIN KINASES; PROTEIN BINDING; PROTO-ONCOGENE PROTEINS C-RAF; PROTO-ONCOGENE PROTEINS P21(RAS); REPRODUCIBILITY OF RESULTS; RESPONSE ELEMENTS; RNA INTERFERENCE; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES; TRANSCRIPTION, GENETIC;

EID: 84897568295     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2013-07-515957     Document Type: Article

References (75)

1. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell. 2010;142(1):24-38.
2. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090-2093. (Pubitemid 40007660)
3. Bridle KR, Frazer DM, Wilkins SJ, et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet. 2003;361(9358):669-673. (Pubitemid 36246550)
4. Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C. Hepcidin is decreased in TFR2 hemochromatosis. Blood. 2005;105(4):1803-1806. (Pubitemid 40223705)
5. Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet. 2004;36(1):77-82. (Pubitemid 38056211)
6. Roetto A, Papanikolaou G, Politou M, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003;33(1):21-22. (Pubitemid 36068676)
7. Rochette J, Le Gac G, Lassoued K, Férec C, Robson KJ. Factors influencing disease phenotype and penetrance in HFE haemochromatosis. Hum Genet. 2010;128(3):233-248.
8. Fleming RE, Holden CC, Tomatsu S, et al. Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosis. Proc Natl Acad Sci USA. 2001;98(5):2707-2711. (Pubitemid 32209547)
9. Bensaid M, Fruchon S, Mazères C, Bahram S, Roth MP, Coppin H. Multigenic control of hepatic iron loading in a murine model of hemochromatosis. Gastroenterology. 2004;126(5):1400-1408. (Pubitemid 38552803)
10. Papanikolaou G, Tzilianos M, Christakis JI, et al. Hepcidin in iron overload disorders. Blood. 2005;105(10):4103-4105. (Pubitemid 40656161)
11. Martinelli N, Traglia M, Campostrini N, et al. Increased serum hepcidin levels in subjects with the metabolic syndrome: a population study. PLoS ONE. 2012;7(10):e48250.
12. Rajpathak SN, Crandall JP, Wylie-Rosett J, Kabat GC, Rohan TE, Hu FB. The role of iron in type 2 diabetes in humans. Biochim Biophys Acta. 2009;1790(7):671-681.
13. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113(9):1271-1276. (Pubitemid 39069926)
14. Verga Falzacappa MV, Vujic Spasic M, Kessler R, Stolte J, Hentze MW, Muckenthaler MU. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood. 2007;109(1):353-358. (Pubitemid 46053077)
15. Finberg KE, Heeney MM, Campagna DR, et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet. 2008;40(5):569-571. (Pubitemid 351601217)
16. Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood. 2006;108(9):3204-3209.
17. Nohe A, Keating E, Knaus P, Petersen NO. Signal transduction of bone morphogenetic protein receptors. Cell Signal. 2004;16(3):291-299. (Pubitemid 37542404)
18. Casanovas G, Mleczko-Sanecka K, Altamura S, Hentze MW, Muckenthaler MU. Bone morphogenetic protein (BMP)-responsive elements located in the proximal and distal hepcidin promoter are critical for its response to HJV/BMP/SMAD. J Mol Med (Berl). 2009;87(5):471-480.
19. Andriopoulos B Jr, Corradini E, Xia Y, et al. BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet. 2009;41(4):482-487.
20. Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth MP. Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet. 2009;41(4):478-481.
21. Verga Falzacappa MV, Casanovas G, Hentze MW, Muckenthaler MU. A bone morphogenetic protein (BMP)-responsive element in the hepcidin promoter controls HFE2-mediated hepatic hepcidin expression and its response to IL-6 in cultured cells. J Mol Med (Berl). 2008;86(5):531-540.
22. Wang RH, Li C, Xu X, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005;2(6):399-409.
23. Ryan JD, Ryan E, Fabre A, Lawless MW, Crowe J. Defective bone morphogenic protein signaling underlies hepcidin deficiency in HFE hereditary hemochromatosis. Hepatology. 2010;52(4):1266-1273.
24. Kautz L, Meynard D, Besson-Fournier C, et al. BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression. Blood. 2009;114(12):2515-2520.
25. Corradini E, Garuti C, Montosi G, et al. Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis. Gastroenterology. 2009;137(4):1489-1497.
26. Wallace DF, Summerville L, Crampton EM, Frazer DM, Anderson GJ, Subramaniam VN. Combined deletion of Hfe and transferrin receptor 2 in mice leads to marked dysregulation of hepcidin and iron overload. Hepatology. 2009;50(6):1992-2000.
27. Silvestri L, Pagani A, Nai A, De Domenico I, Kaplan J, Camaschella C. The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab. 2008;8(6):502-511.
28. Du X, She E, Gelbart T, et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science. 2008;320(5879):1088-1092. (Pubitemid 351929552)
29. Mleczko-Sanecka K, Casanovas G, Ragab A, et al. SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression. Blood. 2010;115(13):2657-2665.
30. Peyssonnaux C, Zinkernagel AS, Schuepbach RA, et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest. 2007;117(7):1926-1932. (Pubitemid 47036326)
31. Pinto JP, Ribeiro S, Pontes H, et al. Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBPalpha. Blood. 2008;111(12):5727-5733.
32. Tanno T, Bhanu NV, Oneal PA, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13(9):1096-1101. (Pubitemid 47517510)
33. Tanno T, Porayette P, Sripichai O, et al. Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells. Blood. 2009;114(1):181-186.
34. Goodnough JB, Ramos E, Nemeth E, Ganz T. Inhibition of hepcidin transcription by growth factors. Hepatology. 2012;56(1):291-299.
35. Guo W, Bachman E, Li M, et al. Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells. Aging Cell. 2013;12(2):280-291.
36. Latour C, Kautz L, Besson-Fournier C, et al. Testosterone perturbs systemic iron balance through activation of EGFR signaling in the liver and repression of hepcidin [published online ahead of print August 1, 2013]. Hepatology. 2013. doi:10.1002/hep.26648.
37. Godoy P, Hewitt NJ, Albrecht U, et al. Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Arch Toxicol. 2013;87(8):1315-1530.
38. Huard J, Mueller S, Gilles ED, Klingmüller U, Klamt S. An integrative model links multiple inputs and signaling pathways to the onset of DNA synthesis in hepatocytes. FEBS J. 2012;279(18):3290-3313.
39. Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem. 2000;275(26):19906-19912. (Pubitemid 30441595)
40. Raval A, Tanner SM, Byrd JC, et al. Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell. 2007;129(5):879-890. (Pubitemid 46813150)
41. Lapinski PE, Bauler TJ, Brown EJ, Hughes ED, Saunders TL, King PD. Generation of mice with a conditional allele of the p120 Ras GTPase-activating protein. Genesis. 2007;45(12):762-767. (Pubitemid 351158378)
42. Vujić Spasić M, Kiss J, Herrmann T, et al. Hfe acts in hepatocytes to prevent hemochromatosis. Cell Metab. 2008;7(2):173-178. (Pubitemid 351168556)
43. Boutros M, Brás LP, Huber W. Analysis of cell-based RNAi screens. Genome Biol. 2006;7(7):R66.
44. Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4(1):44-57.
45. Szklarczyk D, Franceschini A, Kuhn M, et al. The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res. 2011;39(Database issue):D561-D568.
46. Cline MS, Smoot M, Cerami E, et al. Integration of biological networks and gene expression data using Cytoscape. Nat Protoc. 2007;2(10):2366-2382.
47. Loebke C, Sueltmann H, Schmidt C, et al. Infrared-based protein detection arrays for quantitative proteomics. Proteomics. 2007;7(4):558-564. (Pubitemid 46362619)
48. Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol. 2004;5(10):836-847. (Pubitemid 39336277)
49. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274-293.
50. Dufour J-F, Clavien P-A. Signaling pathways in liver diseases. 2nd ed. New York, NY: Springer-Verlag; 2009.
51. Lapinski PE, Kwon S, Lubeck BA, et al. RASA1 maintains the lymphatic vasculature in a quiescent functional state in mice. J Clin Invest. 2012;122(2):733-747.
52. Pichler I, Minelli C, Sanna S, et al. Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels. Hum Mol Genet. 2011;20(6):1232-1240.
53. Grant GR, Robinson SW, Edwards RE, et al. Multiple polymorphic loci determine basal hepatic and splenic iron status in mice. Hepatology. 2006;44(1):174-185. (Pubitemid 44049150)
54. Jones BC, Beard JL, Gibson JN, et al. Systems genetic analysis of peripheral iron parameters in the mouse. Am J Physiol Regul Integr Comp Physiol. 2007;293(1):R116-R124. (Pubitemid 47092169)
55. Mascareno E, Dhar M, Siddiqui MA. Signal transduction and activator of transcription (STAT) protein-dependent activation of angiotensinogen promoter: a cellular signal for hypertrophy in cardiac muscle. Proc Natl Acad Sci USA. 1998;95(10):5590-5594.
56. Goodman RH, Smolik S. CBP/p300 in cell growth, transformation, and development. Genes Dev. 2000;14(13):1553-1577. (Pubitemid 30460905)
57. Natesan S, Gilman M. YY1 facilitates the association of serum response factor with the c-fos serum response element. Mol Cell Biol. 1995;15(11):5975-5982.
58. Gordon S, Akopyan G, Garban H, Bonavida B. Transcription factor YY1: structure, function, and therapeutic implications in cancer biology. Oncogene. 2006;25(8):1125-1142.
59. Lee KH, Evans S, Ruan TY, Lassar AB. SMAD-mediated modulation of YY1 activity regulates the BMP response and cardiac-specific expression of a GATA4/5/6-dependent chick Nkx2.5 enhancer. Development. 2004;131(19):4709-4723. (Pubitemid 39433458)
60. Efimova T, Deucher A, Kuroki T, Ohba M, Eckert RL. Novel protein kinase C isoforms regulate human keratinocyte differentiation by activating a p38 delta mitogen-activated protein kinase cascade that targets CCAAT/enhancer-binding protein alpha. J Biol Chem. 2002;277(35):31753-31760. (Pubitemid 34968979)
61. Bernards A. GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. Biochim Biophys Acta. 2003;1603(2):47-82. (Pubitemid 36262941)
62. Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: critical elements in the control of small G proteins. Cell. 2007;129(5):865-877. (Pubitemid 46802708)
63. Boon LM, Mulliken JB, Vikkula M. RASA1: variable phenotype with capillary and arteriovenous malformations. Curr Opin Genet Dev. 2005;15(3):265-269. (Pubitemid 40726049)
64. Gallione CJ, Repetto GM, Legius E, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004;363(9412):852-859. (Pubitemid 38368834)
65. Ramey G, Deschemin JC, Vaulont S. Cross-talk between the mitogen activated protein kinase and bone morphogenetic protein/hemojuvelin pathways is required for the induction of hepcidin by holotransferrin in primary mouse hepatocytes. Haematologica. 2009;94(6):765-772.
66. Tang CH, Chen CF, Chen WM, Fong YC. IL-6 increases MMP-13 expression and motility in human chondrosarcoma cells. J Biol Chem. 2011;286(13):11056-11066.
67. Qiu XB, Goldberg AL. Nrdp1/FLRF is a ubiquitin ligase promoting ubiquitination and degradation of the epidermal growth factor receptor family member, ErbB3. Proc Natl Acad Sci USA. 2002;99(23):14843-14848. (Pubitemid 35334571)
68. Espeillac C, Mitchell C, Celton-Morizur S, et al. S6 kinase 1 is required for rapamycin-sensitive liver proliferation after mouse hepatectomy. J Clin Invest. 2011;121(7):2821-2832.
69. Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology. 2008;48(6):2047-2063.
70. Miura K, Taura K, Kodama Y, Schnabl B, Brenner DA. Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity. Hepatology. 2008;48(5):1420-1429.
71. Darshan D, Frazer DM, Anderson GJ. Molecular basis of iron-loading disorders. Expert Rev Mol Med. 2010;12:e36.
72. Maegdefrau U, Arndt S, Kivorski G, Hellerbrand C, Bosserhoff AK. Downregulation of hemojuvelin prevents inhibitory effects of bone morphogenetic proteins on iron metabolism in hepatocellular carcinoma. Lab Invest. 2011;91(11):1615-1623.
73. Llovet JM, Ricci S, Mazzaferro V, et al SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390.
74. Sam AH, Busbridge M, Amin A, et al. Hepcidin levels in diabetes mellitus and polycystic ovary syndrome. Diabet Med. 2013;30(12):1495-1499.
75. Sofroniadou S, Kassimatis T, Goldsmith D. Anaemia, microcytosis and sirolimus - is iron the missing link? Nephrol Dial Transplant. 2010;25(5):1667-1675.