Nur77转录调控靶基因的鉴定及其生理功能的初步研究
摘要
Nur77是核受体家族的成员,它作为转录因子参与了许多生物学过程。由于Nur77的天然配体尚未找到,因而又称孤儿受体(Orphan receptor)。我们实验室先前的研究发现,在TCR/CD3介导的T淋巴细胞激活诱导的细胞凋亡(Activation-induced celldeath,AICD)过程中,Nur77表达持续增加;另外,其他实验室的研究发现,Nur77参与调节T细胞发育、炎症反应、类固醇激素合成、肝细胞糖代谢和肿瘤细胞凋亡等,具有广泛的生理作用。迄今为止,人们已经找到了一些受到Nur77直接转录调控的基因,但它们尚不能全面阐释Nur77在不同生理病理过程特别是T细胞发育和炎症反应中的功能及机制。
本论文从寻找Nur77新的靶基因入手,研究Nur77及其所调控基因的生物学功能,并试图阐释它们所参与的生物学过程的发生机制。
研究表明,Nur77的反式作用元件NBRE(AAAGGTCA)具有高度保守性,存在于多数受Nur77转录调控的基因启动子中,我们采用搜索启动子中含NBRE的所有基因→进行生物信息学分析→实验验证→功能研究的研究策略,寻找鉴定Nur77转录调控的靶基因。
首先,我们从DBTSS数据库中下载得到人类全基因组基因的5'近端启动子序列——[—1000,+200](相对于数据库中默认转录起始位点TSS的位置)。进而使用Perl计算机语言编写NBRE的扫描程序,并对全基因组启动子序列进行逐条扫描,搜索到了483个基因启动子中含有NBRE。根据Nur77的已知功能,选择其中14个基因进行进一步研究:将其启动子序列构建到萤光素酶报告基因载体中,与Nur77的表达载体共转染HEK 293T细胞,分析Nur77对各启动子的转录激活活性,结果获得了三个受Nur77激活的基因启动子,即SerpinA3、ESR1和HSD3B2。其中HSD3B2为已知的Nur77靶基因,SerpinA3和ESR1是两个新的候选基因。
然后,我们在乳腺癌细胞MCF-7和肝癌细胞HepG2中分别使Nur77过表达,分析Nur77过表达对这两个候选基因表达的影响。结果显示,在MCF-7细胞中,Nur77过表达对ESR1的表达没有影响,而在HepG2细胞中,Nur77过表达对SerpinA3的表达具有明显的促进作用。提示SerpinA3可能是受Nur77转录调控的靶基因。
我们进一步应用萤光素酶报告基因技术,在多个细胞系(HEK 293T、SH-SY5Y、HepG2、SMMC-7721、PHH、LNCaP和PC-3)中证实了Nur77对SerpinA3启动子具有激活作用。另外,在HEK 293T细胞中发现,SerpinA3启动子中除NBRE(—182～—175)以外,还存在一个NBRE样元件(—93～—88),对Nur77激活SerpinA3的转录有所贡献。但该NBRE样元件在HepG2细胞中无明显作用,提示该NBRE样元件受Nur77的激活作用可能具有细胞特异性。
EMSA实验证明,Nur77可与SerpinA3启动子中的NBRE(—182～—175)元件发生特异的结合。ChIP实验证明在HepG2细胞中,内源性表达的Nur77也可与SerpinA3启动子结合。至此我们基本可以得出结论,Nur77对SerpinA3基因存在转录激活作用。
接着,我们进行了基因表达调控的具体研究,发现在HepG2细胞中Nur77可调节SerpinA3的基础表达。Nur77过量表达(野生型和融合蛋白EGFP-Nur77)可以显著上调内源性SerpinA3的表达水平:RNAi抑制Nur77表达则可显著下调内源性SerpinA3 mRNA和蛋白质的表达水平。
文献报道,IL-6可诱导肝细胞中SerpinA3的表达,STAT3在该过程中发挥重要作用。我们的研究发现,NBRE(—182～—175)的缺失会显著削弱IL-6对SerpinA3启动子的激活作用,这提示,IL-6刺激时Nur77对SerpinA3的转录激活具有调节作用。进一步研究发现,IL-6处理细胞后Nur77表达总量以及核内含量都有所增加;当过量表达显性负Nur77(M3)后,IL-6激活SerpinA3的作用被降低。以上证据证明,在HepG2细胞中Nur77参与调节IL-6诱导的SerpinA3的表达。
Nur77对SerpinA3的转录激活作用的其他生物学意义研究发现,在PMA+lonomycin激活的Jurkat T淋巴细胞中,细胞内SerpinA3的表达随Nur77表达水平的变化而呈动态变化。ChIP实验表明,PMA+lonomycin刺激Jurkat细胞后,内源性的Nur77与SerpinA3启动子结合,提示在T细胞活化过程中,Nur77可能通过激活SerpinA3而行使其生物学功能。
结论:本项研究首次证明Nur77对SerpinA3的转录激活作用,为Nur77参与炎症反应调节提供了一个新的证据;首次发现T淋巴细胞激活过程中SerpinA3表达上调的现象;为SerpinA3参与的病理过程,如肿瘤、炎症反应、前列腺癌和Alzheimer's症等的发生发展提供了新的资料。
Nur77 is one member of nuclear receptor family.As a transcription factor,Nur77 participates in a variety of biological processes including T cell development, inflammatory response,steroid hormone synthesis,hepatic glucose metabolism and etc.Our previous report showed that Nur77 was upregulated during the activation-induced cell death(AICD) in T lymphocytes,however,no target gene transactivated by Nur77 is found in this process.In this study,we aim to further understand the functions and mechanisms of Nur77 via searching its novel target genes.
Since cis-element,NBRE,found in almost all known promoters of Nur77-targeted genes is highly conservative we searched the novel Nur77 targeted genes by Genebank data mining for the promoters with NBRE and then validated by various wet-lab experiments.
We produced firstly a program NBREscan in Perl,with which we scanned the genome-wide promoter sequences[—1000 bp to +200 bp relative to the TSS] downloaded from DBTSS database for the genes with NBREs in their promoters. We found 483 candidate genes,from which we selected 14 function-associated genes to construct the promoter-Luciferase report plasmids.Cotransfection of HEK 293T cells with Nur77 expression vector and the report plasmids demonstrated that three genes with NBREs in their promoters were transactivated by Nur77,i.e.,one known target gene of Nur77,HSD3B2,and two novel ones,ESR1 and SerpinA3.
We then identified the transcriptional regulation of the two novel genes by Nur77 in proper cell lines.As the result,SerpinA3 expression,but not ESR1,was upregulated by Nur77 in HepG2 cells,indicating that ESR1 might not be a Nur77 regultated gene.We thereafter focused our attention on the transactivation of SerpinA3 by Nur77 in detail.
After the transactivation of SerpinA3 promoter by Nur77 was confirmed in several cell lines,EMSA(electrophoretic mobility shift assay) demonstrated that Nur77 was bound specifically with NBRE(—182 to—175) in the SerpinA3 promoter,suggesting that the NBRE in SerpinA3 promoter is a Nur77-dependent functional motif.In addition,a NBRE-like element(—93 to—88) was found to be contributed to the transactivation by Nur77.ChIP(chromatin immunoprecipitation) assay revealed that both endogenous and exogenous expressed Nur77 were bound with the SerpinA3 promoter in HepG2 cells.These data allowed us draw a conclusion that Nur77 transactivates SerpinA3 expression.
We further investigated the transcription and regulation of SperinA3 in HepG2 cells.It was found that Nur77 regulated basal expression of SerpinA3 in HepG2 cells.Over-expression of both wild-type Nur77 and EGFP-Nur77 fusion proteins augmented the basal expression of SerpinA3,while knockdown of Nur77 via RNA interference supressed its expression in HepG2 cells.These data indicated that Nur77 is involved in the regulation of SerpinA3 basal expression in the HepG2 human liver cancer cells.
Studies on IL-6-induced SerpinA3 expression demonstrated that Nur77 enhanced IL-6-induced SerpinA3 expression.Truncation of the NBRE(—182 to—175) impaired the expression of SerpinA3 induced by IL-6.Stimulation of HepG2 cells with IL-6,SerpinA3,total Nur77 and its nuclear content were all increased, while overexpression of the dominant negative Nur77 decreased SerpinA3 expression,suggesting that SerpinA3 expression is kept the pace with the concentration of the nuclear transcription factor Nur77 in cell nuclear.
In order to optimize the expression of SerpinA3 regulated by Nur77,several cell lines were selected and treated with various chemicals.It was found that both Nur77 and SerpinA3 expression in PMA plus Ionomycin-treated Jurkat T lymphocytes were upregulated and their expression change seemed functional-related.ChIP assay confirmed that Nur77 bound with the SerpinA3 promoter in the cells after stimulation,suggesting that Nur77 transactivates SerpinA3 during T cell activation.However,molecular mechanism of this phenomenon remains to be further explored.
In summary,we provided the evidences for the first time that SerpinA3 is a novel target gene of Nur77,and both SerpinA3 and Nur77 may play important roles in physiological and pathological conditions,such as inflammatory response and T cell activation.
本论文从寻找Nur77新的靶基因入手,研究Nur77及其所调控基因的生物学功能,并试图阐释它们所参与的生物学过程的发生机制。
研究表明,Nur77的反式作用元件NBRE(AAAGGTCA)具有高度保守性,存在于多数受Nur77转录调控的基因启动子中,我们采用搜索启动子中含NBRE的所有基因→进行生物信息学分析→实验验证→功能研究的研究策略,寻找鉴定Nur77转录调控的靶基因。
首先,我们从DBTSS数据库中下载得到人类全基因组基因的5'近端启动子序列——[—1000,+200](相对于数据库中默认转录起始位点TSS的位置)。进而使用Perl计算机语言编写NBRE的扫描程序,并对全基因组启动子序列进行逐条扫描,搜索到了483个基因启动子中含有NBRE。根据Nur77的已知功能,选择其中14个基因进行进一步研究:将其启动子序列构建到萤光素酶报告基因载体中,与Nur77的表达载体共转染HEK 293T细胞,分析Nur77对各启动子的转录激活活性,结果获得了三个受Nur77激活的基因启动子,即SerpinA3、ESR1和HSD3B2。其中HSD3B2为已知的Nur77靶基因,SerpinA3和ESR1是两个新的候选基因。
然后,我们在乳腺癌细胞MCF-7和肝癌细胞HepG2中分别使Nur77过表达,分析Nur77过表达对这两个候选基因表达的影响。结果显示,在MCF-7细胞中,Nur77过表达对ESR1的表达没有影响,而在HepG2细胞中,Nur77过表达对SerpinA3的表达具有明显的促进作用。提示SerpinA3可能是受Nur77转录调控的靶基因。
我们进一步应用萤光素酶报告基因技术,在多个细胞系(HEK 293T、SH-SY5Y、HepG2、SMMC-7721、PHH、LNCaP和PC-3)中证实了Nur77对SerpinA3启动子具有激活作用。另外,在HEK 293T细胞中发现,SerpinA3启动子中除NBRE(—182～—175)以外,还存在一个NBRE样元件(—93～—88),对Nur77激活SerpinA3的转录有所贡献。但该NBRE样元件在HepG2细胞中无明显作用,提示该NBRE样元件受Nur77的激活作用可能具有细胞特异性。
EMSA实验证明,Nur77可与SerpinA3启动子中的NBRE(—182～—175)元件发生特异的结合。ChIP实验证明在HepG2细胞中,内源性表达的Nur77也可与SerpinA3启动子结合。至此我们基本可以得出结论,Nur77对SerpinA3基因存在转录激活作用。
接着,我们进行了基因表达调控的具体研究,发现在HepG2细胞中Nur77可调节SerpinA3的基础表达。Nur77过量表达(野生型和融合蛋白EGFP-Nur77)可以显著上调内源性SerpinA3的表达水平:RNAi抑制Nur77表达则可显著下调内源性SerpinA3 mRNA和蛋白质的表达水平。
文献报道,IL-6可诱导肝细胞中SerpinA3的表达,STAT3在该过程中发挥重要作用。我们的研究发现,NBRE(—182～—175)的缺失会显著削弱IL-6对SerpinA3启动子的激活作用,这提示,IL-6刺激时Nur77对SerpinA3的转录激活具有调节作用。进一步研究发现,IL-6处理细胞后Nur77表达总量以及核内含量都有所增加;当过量表达显性负Nur77(M3)后,IL-6激活SerpinA3的作用被降低。以上证据证明,在HepG2细胞中Nur77参与调节IL-6诱导的SerpinA3的表达。
Nur77对SerpinA3的转录激活作用的其他生物学意义研究发现,在PMA+lonomycin激活的Jurkat T淋巴细胞中,细胞内SerpinA3的表达随Nur77表达水平的变化而呈动态变化。ChIP实验表明,PMA+lonomycin刺激Jurkat细胞后,内源性的Nur77与SerpinA3启动子结合,提示在T细胞活化过程中,Nur77可能通过激活SerpinA3而行使其生物学功能。
结论:本项研究首次证明Nur77对SerpinA3的转录激活作用,为Nur77参与炎症反应调节提供了一个新的证据;首次发现T淋巴细胞激活过程中SerpinA3表达上调的现象;为SerpinA3参与的病理过程,如肿瘤、炎症反应、前列腺癌和Alzheimer's症等的发生发展提供了新的资料。
Nur77 is one member of nuclear receptor family.As a transcription factor,Nur77 participates in a variety of biological processes including T cell development, inflammatory response,steroid hormone synthesis,hepatic glucose metabolism and etc.Our previous report showed that Nur77 was upregulated during the activation-induced cell death(AICD) in T lymphocytes,however,no target gene transactivated by Nur77 is found in this process.In this study,we aim to further understand the functions and mechanisms of Nur77 via searching its novel target genes.
Since cis-element,NBRE,found in almost all known promoters of Nur77-targeted genes is highly conservative we searched the novel Nur77 targeted genes by Genebank data mining for the promoters with NBRE and then validated by various wet-lab experiments.
We produced firstly a program NBREscan in Perl,with which we scanned the genome-wide promoter sequences[—1000 bp to +200 bp relative to the TSS] downloaded from DBTSS database for the genes with NBREs in their promoters. We found 483 candidate genes,from which we selected 14 function-associated genes to construct the promoter-Luciferase report plasmids.Cotransfection of HEK 293T cells with Nur77 expression vector and the report plasmids demonstrated that three genes with NBREs in their promoters were transactivated by Nur77,i.e.,one known target gene of Nur77,HSD3B2,and two novel ones,ESR1 and SerpinA3.
We then identified the transcriptional regulation of the two novel genes by Nur77 in proper cell lines.As the result,SerpinA3 expression,but not ESR1,was upregulated by Nur77 in HepG2 cells,indicating that ESR1 might not be a Nur77 regultated gene.We thereafter focused our attention on the transactivation of SerpinA3 by Nur77 in detail.
After the transactivation of SerpinA3 promoter by Nur77 was confirmed in several cell lines,EMSA(electrophoretic mobility shift assay) demonstrated that Nur77 was bound specifically with NBRE(—182 to—175) in the SerpinA3 promoter,suggesting that the NBRE in SerpinA3 promoter is a Nur77-dependent functional motif.In addition,a NBRE-like element(—93 to—88) was found to be contributed to the transactivation by Nur77.ChIP(chromatin immunoprecipitation) assay revealed that both endogenous and exogenous expressed Nur77 were bound with the SerpinA3 promoter in HepG2 cells.These data allowed us draw a conclusion that Nur77 transactivates SerpinA3 expression.
We further investigated the transcription and regulation of SperinA3 in HepG2 cells.It was found that Nur77 regulated basal expression of SerpinA3 in HepG2 cells.Over-expression of both wild-type Nur77 and EGFP-Nur77 fusion proteins augmented the basal expression of SerpinA3,while knockdown of Nur77 via RNA interference supressed its expression in HepG2 cells.These data indicated that Nur77 is involved in the regulation of SerpinA3 basal expression in the HepG2 human liver cancer cells.
Studies on IL-6-induced SerpinA3 expression demonstrated that Nur77 enhanced IL-6-induced SerpinA3 expression.Truncation of the NBRE(—182 to—175) impaired the expression of SerpinA3 induced by IL-6.Stimulation of HepG2 cells with IL-6,SerpinA3,total Nur77 and its nuclear content were all increased, while overexpression of the dominant negative Nur77 decreased SerpinA3 expression,suggesting that SerpinA3 expression is kept the pace with the concentration of the nuclear transcription factor Nur77 in cell nuclear.
In order to optimize the expression of SerpinA3 regulated by Nur77,several cell lines were selected and treated with various chemicals.It was found that both Nur77 and SerpinA3 expression in PMA plus Ionomycin-treated Jurkat T lymphocytes were upregulated and their expression change seemed functional-related.ChIP assay confirmed that Nur77 bound with the SerpinA3 promoter in the cells after stimulation,suggesting that Nur77 transactivates SerpinA3 during T cell activation.However,molecular mechanism of this phenomenon remains to be further explored.
In summary,we provided the evidences for the first time that SerpinA3 is a novel target gene of Nur77,and both SerpinA3 and Nur77 may play important roles in physiological and pathological conditions,such as inflammatory response and T cell activation.
引文
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35. Inoue H, Okayama H and Okayama H. High efficiency transformation ofs Escherichia coli with plasmids. Gene. 1990; 96(1): 23-28.
36. Mynard V, Latchoumanin O, Guignat L, et al. Synergistic Signaling by Corticotropin-Releasing Hormone and Leukemia Inhibitory Factor Bridged by Phosphorylated 3',5'-Cyclic Adenosine Monophosphate Response Element Binding Protein at the Nur Response Element (NurRE)-Signal Transducers and Activators of Transcription (STAT) Element of the Proopiomelanocortin Promoter. Mol. Endocrinol. 2004; 18(12): 2997-3010.
37. Kordula T, Rydel RE, Brigham EF, et al. Oncostatin M and the Interleukin-6 and Soluble Interleukin-6 Receptor Complex Regulate a1-Antichymotrypsin Expression in Human Cortical Astrocytes. J. Biol. Chem. 1998; 273(7): 4112-4118.
38. Gopalan SM, Wilczynska KM, Konik BS, et al. Astrocyte-specific expression of the alpha1-antichymotrypsin and glial fibrillary acidic protein genes requires activator protein-1. J Biol Chem. 2006; 281(4): 1956-63.
39. Woronicz JD, Lina A, Calnan BJ, et al. Regulation of the Nur77 orphan steroid receptor in activation-induced apoptosis. Mol Cell Biol. 1995; 15(11):6364-6376.
40. Liang Y, Li C, Guzman VM, et al. Upregulation of orphan nuclear receptor Nur77 following PGF(2alpha), Bimatoprost, and Butaprost treatments. Essential role of a protein kinase C pathway involved in EP(2) receptor activated Nur77 gene transcription. Br J Pharmacol. 2004; 142(4):737-748.
41. Guo ZS, Naik A, O'Malley ME, et al. The enhanced tumor selectivity of an oncolytic vaccinia lacking the host range and antiapoptosis genes SPI-1 and SPI-2. Cancer Res. 2005; 65(21): 9991-9998.
42. Bird CH, Sutton VR, Sun J, et al. Selective regulation of apoptosis: the cytotoxic lymphocyte serpin proteinase inhibitor 9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway. Mol Cell Biol. 1998; 18(11): 6387-6398.
43. Brooks MA, Ali AN, Turner PC, et al. A rabbitpox virus serpin gene controls host range by inhibiting apoptosis in restrictive cells. J Virol. 1995; 69(12): 7688-7698.
1.Milbrandt J.Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene.Neuron.1988;1(3):183-188.
2.Nakai A,Kartha S,Sakurai A,et al.A human early response gene homologous to murine nur77 and rat NGFI-B,and related to the nuclear receptor superfamily.Mol Endocrinol.1990;4:1438-1443.
3. Davis IJ, Lau LF. Endocrine and neurogenic regulation of the orphan nuclear receptors Nur 77 and Nurr-1 in the adrenal glands. Mol Cell Biol. 1994; 14:3469-3483.
4. Ohkubo T, Sugawara Y, Sasaki K, et al. Early induction of nerve growth factor-induced genes after liver resection-reperfusion injury. J Hepatol. 2002; 36:210-217.
5. Su Al, Cooke MP, Ching KA, et al. Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci USA. 2002; 99(7):4465-70.
6. Calnan BJ, Szychowski S, Chan FK, et al. A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection. Immunity. 1995; 3(3):273-282.
7. Zhang, J., DeYoung, A., Kasler, et al. Receptor-mediated apoptosis in T. lymphocytes. Cold Spring Harbor Symp. Quant. Biol. 1999; 64, 363-371.
8. Mittelstadt PR, DeFranco AL. Induction of early response genes by cross-linking membrane Ig on B lymphocytes. J Immunol. 1993; 150(11):4822-4832.
9. Woronicz JD, Lina A, Calnan B J, et al. Regulation of the Nur77 orphan steroid receptor in activation-induced apoptosis. Mol Cell Biol. 1995; 15:6364-76.
10. Meinke G, Sigler PB. DNA-binding mechanism of the monomeric orphan nuclear receptor NGFI-B. Nat Struct Biol. 1999; 6(5):471-477.
11. Philips A, Lesage S, Gingras R, et al. Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol Cell Biol. 1997; 17(10):5946-5951.
12. Katagiri Y, Takeda K, Yu ZX, et al. Modulation of retinoid signalling through NGF-induced nuclear export of NGFI-B. Nat Cell Biol. 2000; 2:435-440.
13. Feske S, Giltnane J, Dolmetsch R, et al. Gene regulation mediated by calcium signals in T lymphocytes. Nat Immunol. 2001; 2(4),316-324.
14. Iwata M, Hanaoka S, Sato K. Rescue of thymocytes and T cell hybridomas from glucocorticoid-induced apoptosis by ... Eur J Immunol. 1991; 21(3):643-648.
15. Philips A, Maira M, Mullick A, et al. Antagonism between Nur77 and glucocorticoid receptor for control of transcription Mol. Cell. Biol. 1997; 17: 5952-5959.
16. Amsen D, Calvo CR, Osborne BA, et al. Costimulatory signals are required for induction of transcription factor Nur77 during negative selection of CD4+CD8+ thymocytes. Proc. Natl. Acad. Sci. USA. 1999; 96: 622-627.
17. Vacchio MS, Lee JY, Ashwell JD. Thymus-Derived Glucocorticoids Set the Thresholds for Thymocyte Selection by Inhibiting TCR-Mediated Thymocyte Activation J. Immunol. 1999; 163(3): 1327-1333.
18. Lee SL, Wesselschmidt RL, Linette GP, et al. Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Science. 1995; 269(5223):532-535.
19. Zhou T, Cheng J, Yang P, et al. Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells. J Exp Med. 1996; 183(4): 1879-92.
20. Sohn SJ, Rajpal A, Winoto A. Apoptosis during lymphoid development. Current Opinion in Immunology, 2003; 15(2): 209-216.
21. Fahrner TJ, Carroll SL, Milbrandt J. The NGFI-B protein, an inducible member of the thyroid/sertoid receptor family, is rapidly modified posttranslationally. Mol Cell Biol. 1990; 10(12): 6454-6459.
22. Kolluri SK, Bruey-Sedano N, Cao X, et al. Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in lung cancer cells. Mol Cell Biol. 2003; 23(23):8651-8667.
23. Li Y, Agadir A, Liu R, et al. Molecular determinants of AHPN (CD437)-induced growth arrest and apoptosis in human lung cancer cell lines. Mol Cell Biol. 1998; 18:4719-4731.
24. Lee, J. M., Lee, K.-H., Weidner, et al. Epstein-Barr virus EBNA2 blocks Nur77-mediated apoptosis. Proc. Natl. Acad. Sci. USA. 2002; 99: 11878-11883.
25. Suzuki S, Suzuki N, Mirtsos C, et al. Nur77 as a survival factor in tumor necrosis factor signaling. Proc Natl. Acad. Sci. USA. 2003; 100: 8276-8280.
26. Yimin W, Sagar G, Yoshihiro N, et al. The Orphan Nuclear Receptors NURR1 and NGFI-B Modulate Aromatase Gene Expression in Ovarian Granulosa Cells: A Possible Mechanism for Repression of Aromatase Expression upon Luteinizing Hormone Surge. Endocrinology. 2005; 146: 237-246.
27. Wilson TE, Mouw AR, Weaver CA, et al.The orphan nuclear receptor NGFI-B regulates expression of the gene encoding steroid 21-hydroxylase. Mol Cell Biol. 1993; 13(2): 861-868.
28. Martin LJ, Tremblay JJ. The human 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase type 2 promoter is a novel target for the immediate early orphan nuclear receptor Nur77 in steroidogenic cells. Endocrinology. 2005; 146(2):861-869.
29. Stocco CO, Zhong L, Sugimoto Y, Ichikawa A, Lau LF, Gibori G. Prostaglandin F2alpha-induced expression of 20alpha-hydroxysteroid dehydrogenase involves the transcription factor NUR77. J Biol Chem. 2000; 275(47):37202-11.
30. Pei L, Castrillo A, Chen M, et al. Induction of NR4A Orphan Nuclear Receptor Expression in Macrophages in Response to Inflammatory Stimuli. J Biol Chem. 2005; 280(32): 29256-29262.
31. Pei L, Castrillo A, Tontonoz P. Regulation of Macrophage Inflammatory Gene Expression by the Orphan Nuclear Receptor Nur77. Mol Endocrinol. 2006; 20(4): 786-794.
32. Gruber F, Hufnagl P, Hofer-Warbinek R, et al. Direct binding of Nur77/NAK-1 to the plasminogen activator inhibitor 1 (PAI-1) promoter regulates TNFa-induced PAI-1 expression. Blood 2003; 101(8): 3042-3048.
33. Bonta PI, van Tiel CM, Vos M, et al. Nuclear Receptors Nur77, Nurr1, and NOR-1 Expressed in Atherosclerotic Lesion Macrophages Reduce Lipid Loading and Inflammatory Responses. Arterioscler Thromb Vasc Biol. 2006; 26(10): 2288-2294.
34. Youn HD, Liu JO. Cabin1 represses MEF2-dependent Nur77 expression and T cell apoptosis by controlling association of histone deacetylases and acetylases with MEF2. Immunity. 2000; 13(1):85-94.
35. Ayer DE, Lawrence QA, Eisenman RN. Mad-max transcriptional repression is mediated by ternary complex formation with mammalian homologs of yeast repressor sin3. Cell. 1995; 80(5):767-776.
36. Li J, Lin Q, Wang W, et al. Specific targeting and constitutive association of histone deacetylase complexes during transcriptional repression. Genes Dev. 2002; 16(6): 687-692.
37. Sohn YC, Kwak E, Na Y, et al. Silencing Mediator of Retinoid and Thyroid Hormone Receptors and Activating Signal Cointegrator-2 as Transcriptional Coregulators of the Orphan Nuclear Receptor Nur77. J Biol Chem. 2001; 276(47): 43734 - 43739.
38. Vietor I, Vadivelu SK, Wick N, et al. TIS7 is a novel component of the mammalian SIN3 histone deacetylase complex. EMBO J. 2002; 21:4621-4631.
39. Esau C, Boes M, Youn HD, et al. Deletion of calcineurin and myocyte enhancer factor 2 (MEF2) binding domain of Cabini results in enhanced cytokine gene expression in T cells. J Exp Med 2001 ;194:1449-1459.
40. Zhang CL, McKinsey TA, Olson EN. The transcriptional corepressor MITR is a signal-responsive inhibitor of myogenesis. Proc. Natl. Acad. Sci. USA 2001; 98: 7354-7359.
41. Zhang CL, McKinsey TA, Lu JR, et al. Association of COOH-terminal-binding Protein (CtBP) and MEF2-interacting Transcription Repressor (MITR) Contributes to Transcriptional Repression of the MEF2 Transcription Factor. J Biol Chem, 2001; 276(1): 35 - 39.
42. Choi SJ, Park SY, Han TH. 14-3-3t associates with and activates the MEF2D transcription factor during muscle cell differentiation. Nucleic Acids Res. 2001; 29: 2836-2842.
43. Kasler HG, Victoria J, Duramad O, et al. ERK5 is a novel type of mitogen-activated protein kinase containing a transcriptional activation domain. Mol Cell Biol. 2000; 20: 8382-8389.
44. Scoggin KE, Ulloa A, Nyborg JK. The oncoprotein Tax binds the SRC-1-interacting domain of CBP/p300 to mediate transcriptional activation. Mol Cell Biol. 2001; 21(16):5520-30.
45. Ego T, Ariumi Y, Shimotohno K. The interaction of HTLV-1 Tax with HDAC1 negatively regulates the viral gene expression. Oncogene. 2002; 21(47):7241-6.
46. Chen X, Zachar V, Chang C, et al. Differential expression of Nur77 family members in human T-lymphotropic virus type 1-infected cells: transactivation of the TR3/nur77 gene by Tax protein. J Virol. 1998; 72(8):6902-6.
47. Factor V, Oliver AL, Panta GR, et al. Roles of Akt/PKB and IKK complex in constitutive induction of NF-kappaB in hepatocellular carcinomas of transforming growth factor alpha/c-myc transgenic mice. Hepatology 2001; 34:32-41.
48. Masuyama N, Oishi K, Mori Y, et al. Akt Inhibits the Orphan Nuclear Receptor Nur77 and T-cell Apoptosis. J Biol Chem. 2001; 276: 32799-32805.
49. Pekarsky Y, Hallas C, Palamarchuk A, et al. AKT phosphorylates and regulates the orphan nuclear receptor Nur77. Proc Natl Acad Sci USA. 2001; 98: 3690-3694.
50. Ohkura N, Ito M, Tsukada T, et al. Structure, mapping and expression of a human NOR-1 gene, the third member of the Nur77/NGFI-B family. Biochim Biophys Acta, 1996; 1308:205-214.
51. Maira M, Martens C, Batsche E, et al. Dimer-specific potentiation of NGFI-B (Nur77) transcriptional activity by the protein kinase A pathway and AF-1-dependent coactivator recruitment. Mol Cell Biol. 2003; 23(3):763-76.
52. Sohn YC, Kwak E, Na Y, et al. Silencing mediator of retinoid and thyroid hormone receptors and activating signal cointegrator-2 as transcriptional coregulators of the orphan nuclear receptor Nur77. J Biol Chem. 2001; 276(47):43734-9.
53. Fass DM, Butler JE, Goodman RH. Deacetylase activity is required for cAMP activation of a subset of CREB target genes. J Biol Chem. 2003; 278(44):43014-9.
54. Martin LJ, Tremblay JJ. The human 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase type 2 promoter is a novel target for the immediate early orphan nuclear receptor Nur77 in steroidogenic cells. Endocrinology. 2005; 146(2):861-9.
55. Song KH, Park YY, Park KC, et al. The atypical orphan nuclear receptor DAX-1 interacts with orphan nuclear receptor Nur77 and represses its transactivation. Mol Endocrinol. 2004; 18(8): 1929-40.
56. Perlmann T, Jansson L. A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and Nurr1. Genes Dev. 1995; 9:769 - 782.
57. Wu Q, Li Y, Liu R, et al. Modulation of retinoic acid sensitivity in lung cancer cells through dynamic balance of orphan receptors nur77 and COUP-TF and their heterodimerization. EMBO J. 1997; 16(7): 1656-69.
58. Szegezdi E, Kiss I, Simon A, et al. Ligation of retinoic acid receptor alpha regulates negative selection of thymocytes by inhibiting both DNA binding of nur77 and synthesis of bim. J Immunol. 2003; 170(7):3577-84.
59. Martens C, Bilodeau S, Maira M, et al. Protein-protein interactions and transcriptional antagonism between the subfamily of NGFI-B/Nur77 orphan nuclear receptors and glucocorticoid receptor. Mol Endocrinol. 2005; 19(4):885-97.
60. Yeo MG, Yoo YG, Choi HS, et al. Negative cross-talk between Nur77 and small heterodimer partner and its role in apoptotic cell death of hepatoma cells. Mol Endocrinol. 2005; 19(4):950-63.
61. Park KC, Song KH, Chung HK, et al. CR6-interacting factor 1 interacts with orphan nuclear receptor Nur77 and inhibits its transactivation. Mol Endocrinol. 2005; 19(1): 12-24.
62. Li H, Kolluri S K, Gu J, et al. Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. Science. 2000; 289(5482): 1159-1164.
63. Lin B, Kolluri SK, Lin F, et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell. 2004; 116(4):527-540.
64. Cao X, Liu W, Lin F, et al. Retinoid X receptor regulates Nur77/TR3-dependent apoptosis [corrected] by modulating its nuclear export and mitochondrial targeting. Mol Cell Biol. 2004; 24(22):9705-25.
65. Murphy EP, McEvoy A, Conneely OM, et al. Involvement of the nuclear orphan receptor NURR1 in the regulation of corticotropin-releasing hormone expression and actions in human inflammatory arthritis. Arthritis Rheum. 2001; 44(4): 782-93.
2. Woronicz JD, Lina A, Calnan B J, et al. Regulation of the Nur77 orphan steroid receptor in activation-induced apoptosis. Mol Cell Biol. 1995; 15:6364-76.
3. Lee SL, Wesselschmidt RL, Linette GP, et al. Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Science. 1995; 269(5223):532-535.
4. Zhou T, Cheng J, Yang P, et al. Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells. J Exp Med. 1996; 183(4): 1879-92.
5. Sohn SJ, Rajpal A, Winoto A. Apoptosis during lymphoid development. Current Opinion in Immunology, 2003; 15(2): 209-216.
6. Yimin W, Sagar G, Yoshihiro N, et al. The Orphan Nuclear Receptors NURR1 and NGFI-B Modulate Aromatase Gene Expression in Ovarian Granulosa Cells: A Possible Mechanism for Repression of Aromatase Expression upon Luteinizing Hormone Surge. Endocrinology. 2005; 146: 237-246.
7. Wilson TE, Mouw AR, Weaver CA, et al. The orphan nuclear receptor NGFI-B regulates expression of the gene encoding steroid 21-hydroxylase. Mol Cell Biol. 1993; 13(2): 861-868.
8. Martin LJ, Tremblay JJ. The human 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase type 2 promoter is a novel target for the immediate early orphan nuclear receptor Nur77 in steroidogenic cells. Endocrinology. 2005; 146(2):861-869.
9. Stocco CO, Zhong L, Sugimoto Y, Ichikawa A, Lau LF, Gibori G. Prostaglandin F2alpha-induced expression of 20alpha-hydroxysteroid dehydrogenase involves the transcription factor NUR77. J Biol Chem. 2000; 275(47):37202-11.
10. Murphy EP, McEvoy A, Conneely OM, et al. Involvement of the nuclear orphan receptor NURR1 in the regulation of corticotropin-releasing hormone expression and actions in human inflammatory arthritis. Arthritis Rheum. 2001; 44(4): 782-93.
11. Pei L, Castrillo A, Chen M, et al. Induction of NR4A Orphan Nuclear Receptor Expression in Macrophages in Response to Inflammatory Stimuli. J Biol Chem. 2005; 280(32): 29256-29262.
12. Pei L, Castrillo A, Tontonoz P. Regulation of Macrophage Inflammatory Gene Expression by the Orphan Nuclear Receptor Nur77. Mol Endocrinol. 2006; 20(4): 786-794.
13. Gruber F, Hufnagl P, Hofer-Warbinek R, et al. Direct binding of Nur77/NAK-1 to the plasminogen activator inhibitor 1 (PAI-1) promoter regulates TNFα-induced PAI-1 expression. Blood 2003; 101(8): 3042-3048.
14. Bonta PI, van Tiel CM, Vos M, et al. Nuclear Receptors Nur77, Nurr1, and NOR-1 Expressed in Atherosclerotic Lesion Macrophages Reduce Lipid Loading and Inflammatory Responses. Arterioscler Thromb Vasc Biol. 2006; 26(10): 2288-2294.
15. Kolluri SK, Bruey-Sedano N, Cao X, et al. Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in lung cancer cells. Mol Cell Biol. 2003; 23(23):8651-8667.
16. Li Y, Agadir A, Liu R, et al. Molecular determinants of AHPN (CD437)-induced growth arrest and apoptosis in human lung cancer cell lines. Mol Cell Biol. 1998; 18:4719-4731.
17. Lee, J. M., Lee, K.-H., Weidner, et al. Epstein-Barr virus EBNA2 blocks Nur77-mediated apoptosis. Proc. Natl. Acad. Sci. USA. 2002; 99: 11878-11883.
18. Suzuki S, Suzuki N, Mirtsos C, et al. Nur77 as a survival factor in tumor necrosis factor signaling. Proc Natl. Acad. Sci. USA. 2003; 100: 8276-8280.
19. Li H, Kolluri S K, Gu J, et al. Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. Science. 2000; 289(5482): 1159-1164.
20. Lin B, Kolluri SK, Lin F, et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell. 2004; 116(4):527-540.
21. Yanxin Liu, Yiping He, Jin Zhang, et al. Tyrosine mutation in CD3E-ITAM blocked T lymphocyte apoptosis mediated by CD3ε, Immunol. Invest. 2003; 32 (1-2): 57-68.
22. Stocco CO, Lau LF and Gibori G. A Calcium/Calmodulin-dependent Activation of ERK1/2 Mediates JunD Phosphorylation and Induction of nur77 and 20a-hsd Genes by Prostaglandin F_(2a) in Ovarian Cells. J. Biol. Chem. 2002; 277(5): 3293-3302.
23. Mu X and Chang C. TR3 Orphan Nuclear Receptor Mediates Apoptosis through Up-regulating E2F1 in Human Prostate Cancer LNCaP Cells. J. Biol. Chem. 2003; 278(44): 42840-42845.
24. Robert NM, Martin LJ and Tremblay JJ. The Orphan Nuclear Receptor NR4A1 Regulates Insulin-Like 3 Gene Transcription in Leydig Cells. Biol. Reprod. 2006; 74(2): 322-330.
25. Song KH, Park YY, Kee HJ, et at. Orphan Nuclear Receptor Nur77 Induces Zinc Finger Protein GIOT-1 Gene Expression, and G1OT-1 Acts as a Novel Corepressor of Orphan Nuclear Receptor SF-1 via Recruitment of HDAC2. J. Biol. Chem. 2006; 281(23): 15605-15614.
26. Hiromura M, Suizu F, Narita M, et al. Identification of Nerve Growth Factor-responsive Element of the TCL1 Promoter as a Novel Negative Regulatory Element. J. Biol. Chem. 2006; 281(38): 27753-27764.
27. Philips A, Lesage S, Gingras R, et al. Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol. Cell. Biol. 1997; 17(10): 5946-5951.
28. Perlmann T, Jansson L. A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes Dev. 1995; 9(7): 769-782.
29. Rajpal A, Cho YA, Yelent B, et al. Transcriptional activation of known and novel apoptotic pathways by Nur77 orphan steroid receptor. EMBO J. 2003; 22(24): 6526-6536.
30. Nicola VT, James CS and Fiona CW. Identifying transcriptional targets. Genome Biology 2004; 5(3):210
31. Janciauskiene S, Wright HT. Inflammation, antichymotrypsin, and lipid metabolism: autogenic etiology of Alzheimer's disease. Bioessays. 1998; 20(12): 1039-1046.
32. Kordula T, Bugno M, Rydel RE, et al. Mechanism of interleukin-1- and tumor necrosis factor alpha-dependent regulation of the alpha 1-antichymotrypsin gene in human astrocytes, Journal of Neuroscience. 2000; 20(20): 7510-7516.
33. Naidoo N, Cooperman BS, Wang ZM, et al. Identification of lysines within alpha 1-antichymotrypsin important for DNAbinding. An unusual combination of DNA binding elements, J. Biol. Chem. 1995; 270 (24): 14548-14555.
34. Kilpatrick L, Johnson JL, Nickbarg EB, et al. Inhibition of human neutrophil superoxide generation by alpha 1-antichymotrypsin. J Immunol. 1991; 146(7): 2388-2393.
35. Inoue H, Okayama H and Okayama H. High efficiency transformation ofs Escherichia coli with plasmids. Gene. 1990; 96(1): 23-28.
36. Mynard V, Latchoumanin O, Guignat L, et al. Synergistic Signaling by Corticotropin-Releasing Hormone and Leukemia Inhibitory Factor Bridged by Phosphorylated 3',5'-Cyclic Adenosine Monophosphate Response Element Binding Protein at the Nur Response Element (NurRE)-Signal Transducers and Activators of Transcription (STAT) Element of the Proopiomelanocortin Promoter. Mol. Endocrinol. 2004; 18(12): 2997-3010.
37. Kordula T, Rydel RE, Brigham EF, et al. Oncostatin M and the Interleukin-6 and Soluble Interleukin-6 Receptor Complex Regulate a1-Antichymotrypsin Expression in Human Cortical Astrocytes. J. Biol. Chem. 1998; 273(7): 4112-4118.
38. Gopalan SM, Wilczynska KM, Konik BS, et al. Astrocyte-specific expression of the alpha1-antichymotrypsin and glial fibrillary acidic protein genes requires activator protein-1. J Biol Chem. 2006; 281(4): 1956-63.
39. Woronicz JD, Lina A, Calnan BJ, et al. Regulation of the Nur77 orphan steroid receptor in activation-induced apoptosis. Mol Cell Biol. 1995; 15(11):6364-6376.
40. Liang Y, Li C, Guzman VM, et al. Upregulation of orphan nuclear receptor Nur77 following PGF(2alpha), Bimatoprost, and Butaprost treatments. Essential role of a protein kinase C pathway involved in EP(2) receptor activated Nur77 gene transcription. Br J Pharmacol. 2004; 142(4):737-748.
41. Guo ZS, Naik A, O'Malley ME, et al. The enhanced tumor selectivity of an oncolytic vaccinia lacking the host range and antiapoptosis genes SPI-1 and SPI-2. Cancer Res. 2005; 65(21): 9991-9998.
42. Bird CH, Sutton VR, Sun J, et al. Selective regulation of apoptosis: the cytotoxic lymphocyte serpin proteinase inhibitor 9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway. Mol Cell Biol. 1998; 18(11): 6387-6398.
43. Brooks MA, Ali AN, Turner PC, et al. A rabbitpox virus serpin gene controls host range by inhibiting apoptosis in restrictive cells. J Virol. 1995; 69(12): 7688-7698.
1.Milbrandt J.Nerve growth factor induces a gene homologous to the glucocorticoid receptor gene.Neuron.1988;1(3):183-188.
2.Nakai A,Kartha S,Sakurai A,et al.A human early response gene homologous to murine nur77 and rat NGFI-B,and related to the nuclear receptor superfamily.Mol Endocrinol.1990;4:1438-1443.
3. Davis IJ, Lau LF. Endocrine and neurogenic regulation of the orphan nuclear receptors Nur 77 and Nurr-1 in the adrenal glands. Mol Cell Biol. 1994; 14:3469-3483.
4. Ohkubo T, Sugawara Y, Sasaki K, et al. Early induction of nerve growth factor-induced genes after liver resection-reperfusion injury. J Hepatol. 2002; 36:210-217.
5. Su Al, Cooke MP, Ching KA, et al. Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci USA. 2002; 99(7):4465-70.
6. Calnan BJ, Szychowski S, Chan FK, et al. A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection. Immunity. 1995; 3(3):273-282.
7. Zhang, J., DeYoung, A., Kasler, et al. Receptor-mediated apoptosis in T. lymphocytes. Cold Spring Harbor Symp. Quant. Biol. 1999; 64, 363-371.
8. Mittelstadt PR, DeFranco AL. Induction of early response genes by cross-linking membrane Ig on B lymphocytes. J Immunol. 1993; 150(11):4822-4832.
9. Woronicz JD, Lina A, Calnan B J, et al. Regulation of the Nur77 orphan steroid receptor in activation-induced apoptosis. Mol Cell Biol. 1995; 15:6364-76.
10. Meinke G, Sigler PB. DNA-binding mechanism of the monomeric orphan nuclear receptor NGFI-B. Nat Struct Biol. 1999; 6(5):471-477.
11. Philips A, Lesage S, Gingras R, et al. Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells. Mol Cell Biol. 1997; 17(10):5946-5951.
12. Katagiri Y, Takeda K, Yu ZX, et al. Modulation of retinoid signalling through NGF-induced nuclear export of NGFI-B. Nat Cell Biol. 2000; 2:435-440.
13. Feske S, Giltnane J, Dolmetsch R, et al. Gene regulation mediated by calcium signals in T lymphocytes. Nat Immunol. 2001; 2(4),316-324.
14. Iwata M, Hanaoka S, Sato K. Rescue of thymocytes and T cell hybridomas from glucocorticoid-induced apoptosis by ... Eur J Immunol. 1991; 21(3):643-648.
15. Philips A, Maira M, Mullick A, et al. Antagonism between Nur77 and glucocorticoid receptor for control of transcription Mol. Cell. Biol. 1997; 17: 5952-5959.
16. Amsen D, Calvo CR, Osborne BA, et al. Costimulatory signals are required for induction of transcription factor Nur77 during negative selection of CD4+CD8+ thymocytes. Proc. Natl. Acad. Sci. USA. 1999; 96: 622-627.
17. Vacchio MS, Lee JY, Ashwell JD. Thymus-Derived Glucocorticoids Set the Thresholds for Thymocyte Selection by Inhibiting TCR-Mediated Thymocyte Activation J. Immunol. 1999; 163(3): 1327-1333.
18. Lee SL, Wesselschmidt RL, Linette GP, et al. Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Science. 1995; 269(5223):532-535.
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