Sox2 function as a negative regulator to control HAMP expression
Biological Research - 2015
Tóm tắt
Hepcidin, encoding by HAMP gene, is the pivotal regulator of iron metabolism, controlling the systemic absorption and transportation of irons from intracellular stores. Abnormal levels of HAMP expression alter plasma iron parameters and lead to iron metabolism disorders. Therefore, it is an important goal to understand the mechanisms controlling HAMP gene expression. Overexpression of Sox2 decrease basal expression of HAMP or induced by IL-6 or BMP-2, whereas, knockdown of Sox2 can increase HAMP expression, furthermore, two potential Sox2-binding sites were identified within the human HAMP promoter. Indeed, luciferase experiments demonstrated that deletion of any Sox2-binding site impaired the negative regulation of Sox2 on HAMP promoter transcriptional activity in basal conditions. ChIP experiments showed that Sox2 could directly bind to these sites. Finally, we verified the role of Sox2 to negatively regulate HAMP expression in human primary hepatocytes. We found that Sox2 as a novel factor to bind with HAMP promoter to negatively regulate HAMP expression, which may be further implicated as a therapeutic option for the amelioration of HAMP-overexpression-related diseases, including iron deficiency anemia.
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Tài liệu tham khảo
Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102(3):783–8. doi:10.1182/blood-2003-03-0672.
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(5704):2090–3. doi:10.1126/science.1104742.
Ganz T. Hepcidin and iron regulation, 10 years later. Blood. 2011;117(17):4425–33. doi:10.1182/blood-2011-01-258467.
Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113(9):1271–6. doi:10.1172/JCI20945.
Lee P, Peng H, Gelbart T, Beutler E. The IL-6- and lipopolysaccharide-induced transcription of hepcidin in HFE-, transferrin receptor 2-, and beta 2-microglobulin-deficient hepatocytes. Proc Natl Acad Sci U S A. 2004;101(25):9263–5. doi:10.1073/pnas.0403108101.
Lawen A, Lane DJ. Mammalian iron homeostasis in health and disease: uptake, storage, transport, and molecular mechanisms of action. Antioxid Redox Signal. 2013;18(18):2473–507. doi:10.1089/ars.2011.4271.
Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352(10):1011–23. doi:10.1056/NEJMra041809.
Andrews NC. Anemia of inflammation: the cytokine-hepcidin link. J Clin Invest. 2004;113(9):1251–3. doi:10.1172/JCI21441.
Hentze MW, Muckenthaler MU, Andrews NC. Balancing acts: molecular control of mammalian iron metabolism. Cell. 2004;117(3):285–97.
Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276(11):7811–9. doi:10.1074/jbc.M008923200.
Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA, et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010;363(12):1146–55. doi:10.1056/NEJMoa1005109.
Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, et al. American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Blood. 2010;116(20):4045–59. doi:10.1182/blood-2010-08-300541.
Wiebe MS, Nowling TK, Rizzino A. Identification of novel domains within Sox-2 and Sox-11 involved in autoinhibition of DNA binding and partnership specificity. J Biol Chem. 2003;278(20):17901–11. doi:10.1074/jbc.M212211200.
Sarkar A, Hochedlinger K. The sox family of transcription factors: versatile regulators of stem and progenitor cell fate. Cell stem cell. 2013;12(1):15–30. doi:10.1016/j.stem.2012.12.007.
Masui S, Nakatake Y, Toyooka Y, Shimosato D, Yagi R, Takahashi K, et al. Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat Cell Biol. 2007;9(6):625–35. doi:10.1038/ncb1589.
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76. doi:10.1016/j.cell.2006.07.024.
Matak P, Chaston TB, Chung B, Srai SK, McKie AT, Sharp PA. Activated macrophages induce hepcidin expression in HuH7 hepatoma cells. Haematologica. 2009;94(6):773–80. doi:10.3324/haematol.2008.003400.
Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276(11):7806–10. doi:10.1074/jbc.M008922200.
De Domenico I, McVey Ward D, Kaplan J. Regulation of iron acquisition and storage: consequences for iron-linked disorders. Nat Rev Mol Cell Biol. 2008;9(1):72–81. doi:10.1038/nrm2295.
Zhang AS, Enns CA. Molecular mechanisms of normal iron homeostasis. Hematology / the Education Program of the American Society of Hematology American Society of Hematology Education Program. 2009:207-14. doi:10.1182/asheducation-2009.1.207.
Goswami T, Andrews NC. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem. 2006;281(39):28494–8. doi:10.1074/jbc.C600197200.
Kawabata H, Fleming RE, Gui D, Moon SY, Saitoh T, O'Kelly J, et al. Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood. 2005;105(1):376–81. doi:10.1182/blood-2004-04-1416.
Zhang AS, Gao J, Koeberl DD, Enns CA. The role of hepatocyte hemojuvelin in the regulation of bone morphogenic protein-6 and hepcidin expression in vivo. J Biol Chem. 2010;285(22):16416–23. doi:10.1074/jbc.M110.109488.
Zhang AS, Yang F, Wang J, Tsukamoto H, Enns CA. Hemojuvelin-neogenin interaction is required for bone morphogenic protein-4-induced hepcidin expression. J Biol Chem. 2009;284(34):22580–9. doi:10.1074/jbc.M109.027318.
Zhang AS. Control of systemic iron homeostasis by the hemojuvelin-hepcidin axis. Adv Nutr. 2010;1(1):38–45. doi:10.3945/an.110.1009.
Zhang AS, Anderson SA, Meyers KR, Hernandez C, Eisenstein RS, Enns CA. Evidence that inhibition of hemojuvelin shedding in response to iron is mediated through neogenin. J Biol Chem. 2007;282(17):12547–56. doi:10.1074/jbc.M608788200.
Du X, She E, Gelbart T, Truksa J, Lee P, Xia Y, et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science. 2008;320(5879):1088–92. doi:10.1126/science.1157121.
Folgueras AR, de Lara FM, Pendas AM, Garabaya C, Rodriguez F, Astudillo A, et al. Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood. 2008;112(6):2539–45. doi:10.1182/blood-2008-04-149773.
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 metabolism. 2008;8(6):502–11. doi:10.1016/j.cmet.2008.09.012.
Mleczko-Sanecka K, Casanovas G, Ragab A, Breitkopf K, Muller A, Boutros M, et al. SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression. Blood. 2010;115(13):2657–65. doi:10.1182/blood-2009-09-238105.
Patel N, Masaratana P, Diaz-Castro J, Latunde-Dada GO, Qureshi A, Lockyer P, et al. BMPER protein is a negative regulator of hepcidin and is up-regulated in hypotransferrinemic mice. J Biol Chem. 2012;287(6):4099–106. doi:10.1074/jbc.M111.310789.
Ring KL, Tong LM, Balestra ME, Javier R, Andrews-Zwilling Y, Li G, et al. Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell stem cell. 2012;11(1):100–9. doi:10.1016/j.stem.2012.05.018.
Lujan E, Chanda S, Ahlenius H, Sudhof TC, Wernig M. Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells. Proc Natl Acad Sci U S A. 2012;109(7):2527–32. doi:10.1073/pnas.1121003109.
Han DW, Tapia N, Hermann A, Hemmer K, Hoing S, Arauzo-Bravo MJ, et al. Direct reprogramming of fibroblasts into neural stem cells by defined factors. Cell stem cell. 2012;10(4):465–72. doi:10.1016/j.stem.2012.02.021.
Kim J, Efe JA, Zhu S, Talantova M, Yuan X, Wang S, et al. Direct reprogramming of mouse fibroblasts to neural progenitors. Proc Natl Acad Sci U S A. 2011;108(19):7838–43. doi:10.1073/pnas.1103113108.
Shi W, Wang H, Pan G, Geng Y, Guo Y, Pei D. Regulation of the pluripotency marker Rex-1 by Nanog and Sox2. J Biol Chem. 2006;281(33):23319–25. doi:10.1074/jbc.M601811200.
Rodda DJ, Chew JL, Lim LH, Loh YH, Wang B, Ng HH, et al. Transcriptional regulation of nanog by OCT4 and SOX2. J Biol Chem. 2005;280(26):24731–7. doi:10.1074/jbc.M502573200.
Aota S, Nakajima N, Sakamoto R, Watanabe S, Ibaraki N, Okazaki K. Pax6 autoregulation mediated by direct interaction of Pax6 protein with the head surface ectoderm-specific enhancer of the mouse Pax6 gene. Dev Biol. 2003;257(1):1–13.
Niwa H, Ogawa K, Shimosato D, Adachi K. A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells. Nature. 2009;460(7251):118–22. doi:10.1038/nature08113.
Doyle SL, Shirey KA, McGettrick AF, Kenny EF, Carpenter S, Caffrey BE, et al. Nuclear factor kappaB2 p52 protein has a role in antiviral immunity through IkappaB kinase epsilon-dependent induction of Sp1 protein and interleukin 15. J Biol Chem. 2013;288(35):25066–75. doi:10.1074/jbc.M113.469122.
Nissen RM, Yamamoto KR. The glucocorticoid receptor inhibits NFkappaB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev. 2000;14(18):2314–29.