Abstract
The orphan receptor NR4Al (Nur77, TR3, NGFI-B) is overexpressed in many different cancer cell lines and tumors, and, in leukemia cells, NR4Al is also more highly expressed than in B- or T-cell. In contrast, we observed the opposite pattern of NR4A2 (Nurrl) expression in these same cells. NR4Al is primarily oncogenic in cancer cell lines and is a target for inhibitors or inactivators and treatment of Jurkat cells with an NR4Al inactivator-induced apoptosis and inhibited cell growth. The in vitro characterization of NR4Al as pro-oncogenic in leukemia cells is in contrast to the tumor suppressor-like activity of NR4Al in transgenic mouse models, and these differences are currently being investigated.
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References
Arkenbout EK, de Waard V, van Bragt M, van Achterberg TA, Grimbergen JM, Pichon B, Pannekoek H, de Vries CJ (2002) Protective function of transcription factor TR3 orphan receptor in atherogenesis: decreased lesion formation in carotid artery ligation model in TR3 transgenic mice. Circulation 106(12):1530–1535
Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ (2006) Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell 126(4):789–799
Bourguet W, Germain P, Gronemeyer H (2000) Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications. Trends Pharmacol Sci 21(10):381–388
Bras A, Albar JP, Leonardo E, de Buitrago GG, Martinez AC (2000) Ceramide-induced cell death is independent of the Fas/Fas ligand pathway and is prevented by Nur77 overexpression in A20 B cells. Cell Death Differ 7(3):262–271
Burris TP, Guo W, McCabe ER (1996) The gene responsible for adrenal hypoplasia congenita, DAX-1, encodes a nuclear hormone receptor that defines a new class within the superfamily. Recent Prog Horm Res 51:241-259; discussion 259–260
Cao X, Liu W, Lin F, Li H, Kolluri SK, Lin B, Han YH, Dawson MI, Zhang XK (2004) Retinoid X receptor regulates Nur77/TR3-dependent apoptosis [corrected] by modulating its nuclear export and mitochondrial targeting. Mol Cell Biol 24(22):9705–9725
Chao LC, Wroblewski K, Zhang Z, Pei L, Vergnes L, Ilkayeva OR, Ding SY, Reue K, Watt MJ, Newgard CB, Pilch PF, Hevener AL, Tontonoz P (2009) Insulin resistance and altered systemic glucose metabolism in mice lacking Nur77. Diabetes 58(12):2788–2796
Chen YL, Jian MH, Lin CC, Kang JC, Chen SP, Lin PC, Hung PJ, Chen JR, Chang WL, Lin SZ, Harn HJ (2008) The induction of orphan nuclear receptor Nur77 expression by n-butylenephthalide as pharmaceuticals on hepatocellular carcinoma cell therapy. Mol Pharmacol 74(4):1046–1058
Cheng LE, Chan FK, Cado D, Winoto A (1997) Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis. EMBO J 16(8):1865–1875
Chinnaiyan P, Varambally S, Tomlins SA, Ray S, Huang S, Chinnaiyan AM, Harari PM (2006) Enhancing the antitumor activity of ErbB blockade with histone deacetylase (HDAC) inhibition. Int J Cancer 118(4):1041–1050
Chintharlapalli S, Burghardt R, Papineni S, Ramaiah S, Yoon K, Safe S (2005a) Activation of Nur77 by selected 1,1-Bis(3’-indolyl)-1-(p-substituted phenyl)methanes induces apoptosis through nuclear pathways. J Biol Chem 280(26):24903–24914
Chintharlapalli S, Papineni S, Baek SJ, Liu S, Safe S (2005b) 1,1-Bis(3’-indolyl)-1-(p-substitutedphenyl)methanes are peroxisome proliferator-activated receptor gamma agonists but decrease HCT-116 colon cancer cell survival through receptor-independent activation of early growth response-1 and nonsteroidal anti-inflammatory drug-activated gene-1. Mol Pharmacol 68(6):1782–1792
Chintharlapalli S, Smith R, 3rd, Samudio I, Zhang W, Safe S (2004) 1,1-Bis(3’-indolyl)-1-(p-substitutedphenyl)methanes induce peroxisome proliferator-activated receptor gamma-mediated growth inhibition, transactivation, and differentiation markers in colon cancer cells. Cancer Res 64(17):5994–6001
Chintharlapalli S, Papineni S, Safe S (2006) 1,1-Bis(3’-indolyl)-1-(p-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through PPARgamma-dependent and PPARgamma-independent pathways. Mol Cancer Ther 5(5):1362–1370
Chintharlapalli S, Papineni S, Safe S (2007) 1,1-bis(3’-indolyl)-1-(p-substitutedphenyl)methanes inhibit growth, induce apoptosis, and decrease the androgen receptor in LNCaP prostate cancer cells through peroxisome proliferator-activated receptor gamma-independent pathways. Mol Pharmacol 71(2):558–569
Cho SD, Yoon K, Chintharlapalli S, Abdelrahim M, Lei P, Hamilton S, Khan S, Ramaiah SK, Safe S (2007) Nur77 agonists induce proapoptotic genes and responses in colon cancer cells through nuclear receptor-dependent and nuclear receptor-independent pathways. Cancer Res 67(2):674–683
Cho SD, Lei P, Abdelrahim M, Yoon K, Liu S, Guo J, Papineni S, Chintharlapalli S, Safe S (2008) 1,1-bis(3’-indolyl)-1-(p-methoxyphenyl)methane activates Nur77-independent proapoptotic responses in colon cancer cells. Mol Carcinog 47(4):252–263
Cho SD, Lee SO, Chintharlapalli S, Abdelrahim M, Khan S, Yoon K, Kamat AM, Safe S (2010) Activation of nerve growth factor-induced B alpha by methylene-substituted diindolylmethanes in bladder cancer cells induces apoptosis and inhibits tumor growth. Mol Pharmacol 77(3):396–404
Contractor R, Samudio IJ, Estrov Z, Harris D, McCubrey JA, Safe SH, Andreeff M, ÂKonopleva M (2005) A novel ring-substituted diindolylmethane,1,1-bis[3’-(5-methoxyindolyl)]-1-(p-t-butylphenyl) methane, inhibits extracellular signal-regulated kinase activation and induces apoptosis in acute myelogenous leukemia. Cancer Res 65(7):2890–2898
Dawson MI, Hobbs PD, Peterson VJ, Leid M, Lange CW, Feng KC, Chen G, Gu J, Li H, Kolluri SK, Zhang X, Zhang Y, Fontana JA (2001) Apoptosis induction in cancer cells by a novel Âanalogue of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid lacking retinoid receptor transcriptional activation activity. Cancer Res 61(12):4723–4730
DeYoung RA, Baker JC, Cado D, Winoto A (2003) The orphan steroid receptor Nur77 family member Nor-1 is essential for early mouse embryogenesis. J Biol Chem 278(47):47104–47109
Dubois C, Hengerer B, Mattes H (2006) Identification of a potent agonist of the orphan nuclear receptor Nurr1. ChemMedChem 1(9):955–958
Eells JB, Misler JA, Nikodem VM (2006) Early postnatal isolation reduces dopamine levels, elevates dopamine turnover and specifically disrupts prepulse inhibition in Nurr1-null heterozygous mice. Neuroscience 140(4):1117–1126
Fassett MS, Jiang W, D’Alise AM, Mathis D, Benoist C (2012) Nuclear receptor Nr4a1 modulates both regulatory T-cell (Treg) differentiation and clonal deletion. Proc Natl Acad Sci U S A 109(10):3891–3896
Ferlini C, Cicchillitti L, Raspaglio G, Bartollino S, Cimitan S, Bertucci C, Mozzetti S, Gallo D, Persico M, Fattorusso C, Campiani G, Scambia G (2009) Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77. Cancer Res 69(17):6906–6914
Gennari A, Bleumink R, Viviani B, Galli CL, Marinovich M, Pieters R, Corsini E (2002) Identification by DNA macroarray of nur77 as a gene induced by di-n-butyltin dichloride: its role in organotin-induced apoptosis. Toxicol Appl Pharmacol 181(1):27–31
Gronemeyer H, Gustafsson JA, Laudet V (2004) Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3(11):950–964
Guo J, Chintharlapalli S, Lee SO, Cho SD, Lei P, Papineni S, Safe S (2010) Peroxisome proliferator-activated receptor gamma-dependent activity of indole ring-substituted 1,1-bis(3’-indolyl)-1-(p-biphenyl)methanes in cancer cells. Cancer Chemother Pharmacol 66(1):141–150
Gurrieri C, Capodieci P, Bernardi R, Scaglioni PP, Nafa K, Rush LJ, Verbel DA, Cordon-Cardo C, Pandolfi PP (2004) Loss of the tumor suppressor PML in human cancers of multiple histologic origins. J Natl Cancer Inst 96(4):269–279
Hintermann S, Chiesi M, von Krosigk U, Mathe D, Felber R, Hengerer B (2007) Identification of a series of highly potent activators of the Nurr1 signaling pathway. Bioorg Med Chem Lett 17(1):193–196
Holmes WF, Soprano DR, Soprano KJ (2003a) Comparison of the mechanism of induction of apoptosis in ovarian carcinoma cells by the conformationally restricted synthetic retinoids CD437 and 4-HPR. J Cell Biochem 89(2):262–278
Holmes WF, Soprano DR, Soprano KJ (2003b) Early events in the induction of apoptosis in ovarian carcinoma cells by CD437: activation of the p38 MAP kinase signal pathway. Oncogene 22(41):6377–6386
Holmes WF, Soprano DR, Soprano KJ (2004) Synthetic retinoids as inducers of apoptosis in ovarian carcinoma cell lines. J Cell Physiol 199(3):317–329
Hong J, Samudio I, Liu S, Abdelrahim M, Safe S (2004) Peroxisome proliferator-activated receptor gamma-dependent activation of p21 in Panc-28 pancreatic cancer cells involves Sp1 and Sp4 proteins. Endocrinology 145(12):5774–5785
Hong J, Samudio I, Chintharlapalli S, Safe S (2008) 1,1-bis(3’-indolyl)-1-(p-substituted phenyl)methanes decrease mitochondrial membrane potential and induce apoptosis in endometrial and other cancer cell lines. Mol Carcinog 47(7):492–507
Ichite N, Chougule MB, Jackson T, Fulzele SV, Safe S, Singh M (2009) Enhancement of docetaxel anticancer activity by a novel diindolylmethane compound in human non-small cell lung cancer. Clin Cancer Res 15(2):543–552
Jeong JH, Park JS, Moon B, Kim MC, Kim JK, Lee S, Suh H, Kim ND, Kim JM, Park YC, Yoo YH (2003) Orphan nuclear receptor Nur77 translocates to mitochondria in the early phase of apoptosis induced by synthetic chenodeoxycholic acid derivatives in human stomach cancer cell line SNU-1. Ann N Y Acad Sci 1010:171–177
Kadkhodaei B, Ito T, Joodmardi E, Mattsson B, Rouillard C, Carta M, Muramatsu S, Sumi-Ichinose C, Nomura T, Metzger D, Chambon P, Lindqvist E, Larsson NG, Olson L, Bjorklund A, Ichinose H, Perlmann T (2009) Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J Neurosci 29(50):15923–15932
Kagaya S, Ohkura N, Tsukada T, Miyagawa M, Sugita Y, Tsujimoto G, Matsumoto K, Saito H, Hashida R (2005) Prostaglandin A2 acts as a transactivator for NOR1 (NR4A3) within the nuclear receptor superfamily. Biol Pharm Bull 28(9):1603–1607
Kassouf W, Chintharlapalli S, Abdelrahim M, Nelkin G, Safe S, Kamat AM (2006) Inhibition of bladder tumor growth by 1,1-bis(3’-indolyl)-1-(p-substitutedphenyl)methanes: a new class of peroxisome proliferator-activated receptor gamma agonists. Cancer Res 66(1):412–418
Ke N, Claassen G, Yu DH, Albers A, Fan W, Tan P, Grifman M, Hu X, Defife K, Nguy V, Meyhack B, Brachat A, Wong-Staal F, Li QX (2004) Nuclear hormone receptor NR4A2 is involved in cell transformation and apoptosis. Cancer Res 64(22):8208–8212
Kolluri SK, Bruey-Sedano N, Cao X, Lin B, Lin F, Han YH, Dawson MI, Zhang XK (2003) Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in lung cancer cells. Mol Cell Biol 23(23):8651–8667
Kolluri SK, Zhu X, Zhou X, Lin B, Chen Y, Sun K, Tian X, Town J, Cao X, Lin F, Zhai D, Kitada S, Luciano F, O’Donnell E, Cao Y, He F, Lin J, Reed JC, Satterthwait AC, Zhang XK (2008) A short Nur77-derived peptide converts Bcl-2 from a protector to a killer. Cancer Cell 14(4):285–298
Lee SL, Wesselschmidt RL, Linette GP, Kanagawa O, Russell JH, Milbrandt J (1995) Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Science 269(5223):532–535
Lee JM, Lee KH, Weidner M, Osborne BA, Hayward SD (2002) Epstein-Barr virus EBNA2 blocks Nur77- mediated apoptosis. Proc Natl Acad Sci U S A 99(18):11878–11883
Lee JM, Lee KH, Farrell CJ, Ling PD, Kempkes B, Park JH, Hayward SD (2004) EBNA2 is required for protection of latently Epstein-Barr virus-infected B cells against specific apoptotic stimuli. J Virol 78(22):12694–12697
Lee KW, Ma L, Yan X, Liu B, Zhang XK, Cohen P (2005) Rapid apoptosis induction by IGFBP-3 involves an insulin-like growth factor-independent nucleomitochondrial translocation of RXRalpha/Nur77. J Biol Chem 280(17):16942–16948
Lee SO, Chintharlapalli S, Liu S, Papineni S, Cho SD, Yoon K, Safe S (2009) p21 expression is induced by activation of nuclear nerve growth factor-induced Balpha (Nur77) in pancreatic cancer cells. Mol Cancer Res 7(7):1169–1178
Lee SO, Abdelrahim M, Yoon K, Chintharlapalli S, Papineni S, Kim K, Wang H, Safe S (2010) Inactivation of the orphan nuclear receptor TR3/Nur77 inhibits pancreatic cancer cell and tumor growth. Cancer Res 70(17):6824–6836
Lee SO, Li X, Khan S, Safe S (2011) Targeting NR4A1 (TR3) in cancer cells and tumors. Expert Opin Ther Targets 15(2):195–206
Lee SO, Andey T, Jin UH, Kim K, Sachdeva M, Safe S (2012) The nuclear receptor TR3 regulates mTORC1 signaling in lung cancer cells expressing wild-type p53. Oncogene 31(27):3265–3276
Lei P, Abdelrahim M, Safe S (2006) 1,1-Bis(3’-indolyl)-1-(p-substituted phenyl)methanes inhibit ovarian cancer cell growth through peroxisome proliferator-activated receptor-dependent and independent pathways. Mol Cancer Ther 5(9):2324–2336
Lei P, Abdelrahim M, Cho SD, Liu S, Chintharlapalli S, Safe S (2008a) 1,1-Bis(3’-indolyl)-1-(p-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through activation of c-jun N-terminal kinase. Carcinogenesis 29(6):1139–1147
Lei P, Abdelrahim M, Cho SD, Liu X, Safe S (2008b) Structure-dependent activation of endoplasmic reticulum stress-mediated apoptosis in pancreatic cancer by 1,1-bis(3’-indoly)-1-(p-substituted phenyl)methanes. Mol Cancer Ther 7(10):3363–3372
Li Y, Lin B, Agadir A, Liu R, Dawson MI, Reed JC, Fontana JA, Bost F, Hobbs PD, Zheng Y, Chen GQ, Shroot B, Mercola D, Zhang XK (1998) Molecular determinants of AHPN (CD437)-induced growth arrest and apoptosis in human lung cancer cell lines. Mol Cell Biol 18(8):4719–4731
Li H, Kolluri SK, Gu J, Dawson MI, Cao X, Hobbs PD, Lin B, Chen G, Lu J, Lin F, Xie Z, Fontana JA, Reed JC, Zhang X (2000) Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. Science 289(5482):1159–1164
Li QX, Ke N, Sundaram R, Wong-Staal F (2006) NR4A1, 2, 3–an orphan nuclear hormone receptor family involved in cell apoptosis and carcinogenesis. Histol Histopathol 21(5):533–540
Li X, Lee SO, Safe S (2012) Structure-dependent activation of NR4A2 (Nurr1) by 1,1-bis(3’-indolyl)-1-(aromatic)methane analogs in pancreatic cancer cells. Biochem Pharmacol 83(10):1445–1455
Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK (2004) Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 116(4):527–540
Liu S, Wu Q, Ye XF, Cai JH, Huang ZW, Su WJ (2002) Induction of apoptosis by TPA and VP-16 is through translocation of TR3. World J Gastroenterol 8(3):446–450
Liu J, Zhou W, Li SS, Sun Z, Lin B, Lang YY, He JY, Cao X, Yan T, Wang L, Lu J, Han YH, Cao Y, Zhang XK, Zeng JZ (2008) Modulation of orphan nuclear receptor Nur77-mediated apoptotic pathway by acetylshikonin and analogues. Cancer Res 68(21):8871–8880
Liu HB, Voso MT, Gumiero D, Duong J, McKendrick JJ, Dear AE (2009) The anti-leukemic effect of a novel histone deacetylase inhibitor MCT-1 and 5-aza-cytidine involves augmentation of Nur77 and inhibition of MMP-9 expression. Int J Oncol 34(2):573–579
Liu JJ, Zeng HN, Zhang LR, Zhan YY, Chen Y, Wang Y, Wang J, Xiang SH, Liu WJ, Wang WJ, Chen HZ, Shen YM, Su WJ, Huang PQ, Zhang HK, Wu Q (2010) A unique pharmacophore for activation of the nuclear orphan receptor Nur77 in vivo and in vitro. Cancer Res 70(9):3628–3637
Liu HB, Mayes PA, Perlmutter P, McKendrick JJ, Dear AE (2011) The anti-leukemic effect and molecular mechanisms of novel hydroxamate and benzamide histone deacetylase inhibitors with 5-aza-cytidine. Int J Oncol 38(5):1421–1425
Maira M, Martens C, Philips A, Drouin J (1999) Heterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activation. Mol Cell Biol 19(11):7549–7557
Maruyama K, Tsukada T, Ohkura N, Bandoh S, Hosono T, Yamaguchi K (1998) The NGFI-B subfamily of the nuclear receptor superfamily (review). Int J Oncol 12(6):1237–1243
Maxwell MA, Muscat GE (2006) The NR4A subgroup: immediate early response genes with pleiotropic physiological roles. Nucl Recept Signal 4:e002
McKenna NJ, Cooney AJ, DeMayo FJ, Downes M, Glass CK, Lanz RB, Lazar MA, Mangelsdorf DJ, Moore DD, Qin J, Steffen DL, Tsai MJ, Tsai SY, Yu R, Margolis RN, Evans RM, O’Malley BW (2009) Minireview: Evolution of NURSA, the Nuclear Receptor Signaling Atlas. Mol Endocrinol 23(6):740–746
Milbrandt J (1988) Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene. Neuron 1(3):183–188
Mullican SE, Zhang S, Konopleva M, Ruvolo V, Andreeff M, Milbrandt J, Conneely OM (2007) Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nat Med 13(6):730–735
Nagel S, Meyer C, Quentmeier H, Kaufmann M, Drexler HG, MacLeod RA (2008) MEF2C is activated by multiple mechanisms in a subset of T-acute lymphoblastic leukemia cell lines. Leukemia 22(3):600–607
Nsegbe E, Wallen-Mackenzie A, Dauger S, Roux JC, Shvarev Y, Lagercrantz H, Perlmann T, Herlenius E (2004) Congenital hypoventilation and impaired hypoxic response in Nurr1 mutant mice. J Physiol 556(Pt 1):43–59
Ordentlich P, Yan Y, Zhou S, Heyman RA (2003) Identification of the antineoplastic agent 6-Âmercaptopurine as an activator of the orphan nuclear hormone receptor Nurr1. J Biol Chem 278(27):24791–24799
Paulsen RF, Granas K, Johnsen H, Rolseth V, Sterri S (1995) Three related brain nuclear receptors, NGFI-B, Nurr1, and NOR-1, as transcriptional activators. J Mol Neurosci 6(4):249–255
Pearen MA, Muscat GE (2010) Minireview: Nuclear hormone receptor 4A signaling: implications for metabolic disease. Mol Endocrinol 24(10):1891–1903
Perlmann T, Jansson L (1995) A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes Dev 9(7):769–782
Philips A, Lesage S, Gingras R, Maira MH, Gauthier Y, Hugo P, Drouin J (1997) Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol Cell Biol 17(10):5946–5951
Pires NM, Pols TW, de Vries MR, van Tiel CM, Bonta PI, Vos M, Arkenbout EK, Pannekoek H, Jukema JW, Quax PH, de Vries CJ (2007) Activation of nuclear receptor Nur77 by 6-Âmercaptopurine protects against neointima formation. Circulation 115(4):493–500
Ponnio T, Conneely OM (2004) nor-1 regulates hippocampal axon guidance, pyramidal cell survival, and seizure susceptibility. Mol Cell Biol 24(20):9070–9078
Ponnio T, Burton Q, Pereira FA, Wu DK, Conneely OM (2002) The nuclear receptor Nor-1 is essential for proliferation of the semicircular canals of the mouse inner ear. Mol Cell Biol 22(3):935–945
Qin C, Morrow D, Stewart J, Spencer K, Porter W, Smith R, 3rd, Phillips T, Abdelrahim M, Samudio I, Safe S (2004) A new class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists that inhibit growth of breast cancer cells: 1,1-Bis(3’-indolyl)-1-(p-substituted phenyl)methanes. Mol Cancer Ther 3(3):247–260
Ramirez-Herrick AM, Mullican SE, Sheehan AM, Conneely OM (2011) Reduced NR4A gene dosage leads to mixed myelodysplastic/myeloproliferative neoplasms in mice. Blood 117(9):2681–2690
Safe S, Kim K, Li X, Lee SO (2011) NR4A orphan receptors and cancer. Nucl Recept Signal 9:e002
Salomoni P, Pandolfi PP (2002) The role of PML in tumor suppression. Cell 108(2):165–170
Sekiya T, Kashiwagi I, Inoue N, Morita R, Hori S, Waldmann H, Rudensky AY, Ichinose H, Metzger D, Chambon P, Yoshimura A (2011) The nuclear orphan receptor Nr4a2 induces Foxp3 and regulates differentiation of CD4+ T cells. Nat Commun 2:269
Seol W, Choi HS, Moore DD (1996) An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science 272(5266):1336–1339
Shi Y (2007) Orphan nuclear receptors in drug discovery. Drug Discov Today 12(11-12):440–445
Shin HJ, Lee BH, Yeo MG, Oh SH, Park JD, Park KK, Chung JH, Moon CK, Lee MO (2004) Induction of orphan nuclear receptor Nur77 gene expression and its role in cadmium-induced apoptosis in lung. Carcinogenesis 25(8):1467–1475
To SK, Zeng JZ, Wong AS (2012) Nur77: a potential therapeutic target in cancer. Expert Opin Ther Targets 16(6):573–585
Vallat L, Magdelenat H, Merle-Beral H, Masdehors P, Potocki de Montalk G, Davi F, Kruhoffer M, Sabatier L, Orntoft TF, Delic J (2003) The resistance of B-CLL cells to DNA damage-induced apoptosis defined by DNA microarrays. Blood 101(11):4598–4606
Wang Z, Benoit G, Liu J, Prasad S, Aarnisalo P, Liu X, Xu H, Walker NP, Perlmann T (2003) Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 423(6939):555–560
Wansa KD, Muscat GE (2005) TRAP220 is modulated by the antineoplastic agent 6-Mercaptopurine, and mediates the activation of the NR4A subgroup of nuclear receptors. J Mol Endocrinol 34(3):835–848
Wansa KD, Harris JM, Muscat GE (2002) The activation function-1 domain of Nur77/NR4A1 mediates trans-activation, cell specificity, and coactivator recruitment. J Biol Chem 277(36):33001–33011
Wansa KD, Harris JM, Yan G, Ordentlich P, Muscat GE (2003) The AF-1 domain of the orphan nuclear receptor NOR-1 mediates trans-activation, coactivator recruitment, and activation by the purine anti-metabolite 6-mercaptopurine. J Biol Chem 278(27):24776–24790
Wilson TE, Fahrner TJ, Johnston M, Milbrandt J (1991) Identification of the DNA binding site for NGFI-B by genetic selection in yeast. Science 252(5010):1296–1300
Wilson TE, Day ML, Pexton T, Padgett KA, Johnston M, Milbrandt J (1992) In vivo mutational analysis of the NGFI-A zinc fingers. J Biol Chem 267(6):3718–3724
Wilson AJ, Arango D, Mariadason JM, Heerdt BG, Augenlicht LH (2003) TR3/Nur77 in colon cancer cell apoptosis. Cancer Res 63(17):5401–5407
Woronicz JD, Calnan B, Ngo V, Winoto A (1994) Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature 367(6460):277–281
Woronicz JD, Lina A, Calnan BJ, Szychowski S, Cheng L, Winoto A (1995) Regulation of the Nur77 orphan steroid receptor in activation-induced apoptosis. Mol Cell Biol 15(11):6364–6376
Wu Q, Liu S, Ye XF, Huang ZW, Su WJ (2002a) Dual roles of Nur77 in selective regulation of apoptosis and cell cycle by TPA and ATRA in gastric cancer cells. Carcinogenesis 23(10):1583–1592
Wu WS, Xu ZX, Ran R, Meng F, Chang KS (2002b) Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions. Oncogene 21(24):3925–3933
Wu H, Lin Y, Li W, Sun Z, Gao W, Zhang H, Xie L, Jiang F, Qin B, Yan T, Chen L, Zhao Y, Cao X, Wu Y, Lin B, Zhou H, Wong AS, Zhang XK, Zeng JZ (2011) Regulation of Nur77 expression by beta-catenin and its mitogenic effect in colon cancer cells. FASEB J 25(1):192–205
Yoon K, Lee SO, Cho SD, Kim K, Khan S, Safe S (2011) Activation of nuclear TR3 (NR4A1) by a diindolylmethane analog induces apoptosis and proapoptotic genes in pancreatic cancer cells and tumors. Carcinogenesis 32(6):836–842
Zetterstrom RH, Solomin L, Mitsiadis T, Olson L, Perlmann T (1996) Retinoid X receptor heterodimerization and developmental expression distinguish the orphan nuclear receptors NGFI-B, Nurr1, and Nor1. Mol Endocrinol 10(12):1656–1666
Zhan Y, Du X, Chen H, Liu J, Zhao B, Huang D, Li G, Xu Q, Zhang M, Weimer BC, Chen D, Cheng Z, Zhang L, Li Q, Li S, Zheng Z, Song S, Huang Y, Ye Z, Su W, Lin SC, Shen Y, Wu Q (2008) Cytosporone B is an agonist for nuclear orphan receptor Nur77. Nat Chem Biol 4 (9):548–556
Zhang XK (2007) Targeting Nur77 translocation. Expert Opin Ther Targets 11(1):69–79
Zhao BX, Chen HZ, Lei NZ, Li GD, Zhao WX, Zhan YY, Liu B, Lin SC, Wu Q (2006) p53 mediates the negative regulation of MDM2 by orphan receptor TR3. EMBO J 25(24):5703–5715
Zhao Y, Howatt DA, Gizard F, Nomiyama T, Findeisen HM, Heywood EB, Jones KL, Conneely OM, Daugherty A, Bruemmer D (2010) Deficiency of the NR4A orphan nuclear receptor NOR1 decreases monocyte adhesion and atherosclerosis. Circ Res 107(4):501–511
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Safe, S., Lee, SO., Meng, C., Zhou, B. (2015). NR4A Orphan Receptors as Drug Targets. In: Andreeff, M. (eds) Targeted Therapy of Acute Myeloid Leukemia. Current Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1393-0_26
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