HPD、NLK调控NF-kB通路和TGFβ通路及机制研究
摘要
本论文包括两部分内容,一是羟苯丙酮酸二加氧酶(hydroxyphenylpyruvate dioxygenase, HPD)正调控NF-κB通路促进肺癌细胞存活和迁移。二是NLK通过Smad4(?)印制TGFβ信号通路活性。
中国有句成语：物以类聚,人以群分。在生物学研究中也适用这样的准则。功能相关的蛋白质通常以相互联系的方式调节复杂的生物学过程。因此,蛋白质相互作用是发现未知蛋白功能或已知蛋白质新功能的重要手段。我们实验室前期利用酵母双杂交技术平台构建了大规模的蛋白质相互作用网络,发现了大量新的蛋白质间相互作用[1]。这个蛋白质相互作用网络为我们提供了很多线索和提示。本课题选取该网络中发现的可能具有重要生物学意义的两对蛋白质间相互作用—HPD与NEMO和NLK与Smad4进行了深入研究。
HPD是酪氨酸分解代谢途径的关键酶[2]。NEMO是NF-κB信号通路的核心分子[3]。采用外源和内源免疫共沉淀实验我们验证了HPD与NEMO的相互作用,确定HPD通过N端与NEMO的N端发生相互作用,并证明HPD可能与IKK组成蛋白质复合体。过表达HPD加速IKBα的降解,促进NF-κB报告基因活性,增加TNFa诱导的NF-κB靶基因BCL-xL、cIAP2、ICAM-1、VCAM-1的表达；利用RNAi敲低HPD表达则抑制NF-κB报告基因的活性；HPD酶活性突变不影响HPD调节NF-κB通路的作用,HPD的催化底物-羟苯丙酮酸(HPP)和催化产物-尿黑酸(HGA)对NF-κB通路也无影响。这些结果说明HPD以不依赖酶活性的方式正调控NF-κB通路。机制上,我们发现过表达HPD可以增强TNFα刺激引起的NEMO泛素化修饰。利用RT-PCR技术检测HPD在小鼠各器官组织的表达,结果显示HPD仅在肝脏和肾脏表达,这与文献报道一致[4]。有意义的是,检测多种细胞系中HPD的表达,发现除肝实质细胞来源细胞系外,多株肺癌细胞中也表达HPD。为进一步验证HPD在肺癌组织中的表达及与NF-κB活性的关系,我们利用免疫组织化学技术检测了HPD及磷酸化p65(S276)在肺癌病人癌组织和癌旁组织中的表达情况,发现HPD在肺癌组织中的表达强度和阳性细胞率都显著高于癌旁肺组织,并与磷酸化p65(S276)的表达呈正相关。进一步,利用慢病毒介导的RNAi敲低肺癌细胞A549和H1299的HPD表达,结果发现HPD下调对肺癌细胞的细胞周期和增殖没有明显影响,但克隆形成实验和Transwell实验结果显示,敲低HPD显著抑制了肺癌细胞的克隆形成能力和迁移能力。综上,我们的实验结果发现HPD在肺癌组织中异常表达,下调其表达可减低肺癌细胞的恶性表型,机制上可能与HPD通过与NEMO的相互作用,以不依赖酶活性的方式激活NF--κB通路有关,提示HPD可能在肺癌的发生发展中起重要作用。
NLK是一种保守的丝／苏氨酸蛋白激酶,识别的保守序列为S/TP基序,通过磷酸化底物的方式参与多种生物学过程[5-9]。采用免疫共沉淀和GST pull down我们证明NLK能与Smad4发生相互作用。进一步,我们初步实验的结果发现NLK以不依赖激酶的方式负调控TGFβ信号通路,机制上可能与促进Smad4的泛素化修饰,降低Smad4(?)勺稳定性有关,但其生物学意义尚有待深入研究。
This essay includes two parts, the first is hydroxyphenylpyruvate dioxygenase (HPD) up-regulates NF-κB signaling pathway and promotes the survival and migra-tion of lung cancer cell, the second is NLK inhibits TGF-β signaling pathway by interacting with Smad4.
It is said that birds of a feather flock together. The principle is also applicable in biology study. Therefore, Finding out the proteins that interact with your interested protein is an important approach to discover its function. Using yeast two-hybrid system, our lab built large scale protein-protein interaction network which included many newly found protein-protein interactions. The interaction network provides a lot of useful information to us. Two pairs of protein-protein interactions discovered by the network that we believed having important function was further studied. The two interactions are that between HPD and NEMO and that between NLK and Smad4.
HPD is the key enzyme of tyrosine catabolism pathway. NEMO is the core protein that involves in NF-κB signaling pathway. Using in vitro and in vivo coimmunoprecipitation assay, we confirmed the interaction between HPD and NEMO through their N terminals, and HPD may form a protein complex with IKK complex. Ectopic expression of HPD accelerated the degradation of IκBα, enhanced the activity of NF-κB reporter and increased the expression of NF-κB target gene induced by TNFα, including BCL-xL, cIAP2, ICAM-1, VCAM-1; knock down of HPD inhibited the activity of NF-κB reporter; lacking of the enzyme activity of HPD didn't influence its function in up-regulating NF-κB pathway, hydroxyphenylpyruvic acid(HPP), the substrate of HPD, and homogentisic acid(HGA), the product of HPD, had little influence on NF-κB pathway. These results indicate HPD up-regulates NF-κB pathway independent of its enzyme activity. We found over-expression of HPD augments the ubiquitination of NEMO stimulated by TNFα. RT-PCR was used to test the expression of HPD in various organs of mice, the result showed that HPD express in liver and kidney, which is consistent with previous report. Intriguingly, besides the cell lines originated from liver, HPD was detected in many lung cancer cell lines. In order to understand the relationship between HPD and NF-κB signaling pathway in lung cancer, we compared the expression of HPD and phosphorylated p65(S276) in the lung tumor tissue and relative normal lung tissue of lung cancer patients, and found lung tumor tissue expressed higher level of HPD than normal lung tissue, the expression of HPD correlate with that of phosphorylated p65(S276). Subsequently, using lentivirus system, knock-down of HPD inhibited the colonic formation ability and migration of H1299and A549and had no influence on the cell cycle and proliferation of H1299and A549. To sum up, our data show lung cancer tissue express HPD, knock-down of HPD alleviate the malignant phenotype of lung cancer, these effects maybe relevant to the interaction between HPD and NEMO and thereby activation of NF-κB pathway. These results indicated HPD may play important role in the initiation and development of lung cancer.
NLK is a conserved S/T protein kinase, recognizes S/TP motif of the target proteins, involves in many biology process through phosphorylating its target proteins. The result from CoIP and GST-pull down showed that NLK interact with Smad4. NLK down-regulate TGFβ pathway independent of its kinase activity through enhancing the ubiquitination of Smad4and decrease the stability of Smad4. The biological significance of the interaction between NLK and Smad4requires further study.
中国有句成语：物以类聚,人以群分。在生物学研究中也适用这样的准则。功能相关的蛋白质通常以相互联系的方式调节复杂的生物学过程。因此,蛋白质相互作用是发现未知蛋白功能或已知蛋白质新功能的重要手段。我们实验室前期利用酵母双杂交技术平台构建了大规模的蛋白质相互作用网络,发现了大量新的蛋白质间相互作用[1]。这个蛋白质相互作用网络为我们提供了很多线索和提示。本课题选取该网络中发现的可能具有重要生物学意义的两对蛋白质间相互作用—HPD与NEMO和NLK与Smad4进行了深入研究。
HPD是酪氨酸分解代谢途径的关键酶[2]。NEMO是NF-κB信号通路的核心分子[3]。采用外源和内源免疫共沉淀实验我们验证了HPD与NEMO的相互作用,确定HPD通过N端与NEMO的N端发生相互作用,并证明HPD可能与IKK组成蛋白质复合体。过表达HPD加速IKBα的降解,促进NF-κB报告基因活性,增加TNFa诱导的NF-κB靶基因BCL-xL、cIAP2、ICAM-1、VCAM-1的表达；利用RNAi敲低HPD表达则抑制NF-κB报告基因的活性；HPD酶活性突变不影响HPD调节NF-κB通路的作用,HPD的催化底物-羟苯丙酮酸(HPP)和催化产物-尿黑酸(HGA)对NF-κB通路也无影响。这些结果说明HPD以不依赖酶活性的方式正调控NF-κB通路。机制上,我们发现过表达HPD可以增强TNFα刺激引起的NEMO泛素化修饰。利用RT-PCR技术检测HPD在小鼠各器官组织的表达,结果显示HPD仅在肝脏和肾脏表达,这与文献报道一致[4]。有意义的是,检测多种细胞系中HPD的表达,发现除肝实质细胞来源细胞系外,多株肺癌细胞中也表达HPD。为进一步验证HPD在肺癌组织中的表达及与NF-κB活性的关系,我们利用免疫组织化学技术检测了HPD及磷酸化p65(S276)在肺癌病人癌组织和癌旁组织中的表达情况,发现HPD在肺癌组织中的表达强度和阳性细胞率都显著高于癌旁肺组织,并与磷酸化p65(S276)的表达呈正相关。进一步,利用慢病毒介导的RNAi敲低肺癌细胞A549和H1299的HPD表达,结果发现HPD下调对肺癌细胞的细胞周期和增殖没有明显影响,但克隆形成实验和Transwell实验结果显示,敲低HPD显著抑制了肺癌细胞的克隆形成能力和迁移能力。综上,我们的实验结果发现HPD在肺癌组织中异常表达,下调其表达可减低肺癌细胞的恶性表型,机制上可能与HPD通过与NEMO的相互作用,以不依赖酶活性的方式激活NF--κB通路有关,提示HPD可能在肺癌的发生发展中起重要作用。
NLK是一种保守的丝／苏氨酸蛋白激酶,识别的保守序列为S/TP基序,通过磷酸化底物的方式参与多种生物学过程[5-9]。采用免疫共沉淀和GST pull down我们证明NLK能与Smad4发生相互作用。进一步,我们初步实验的结果发现NLK以不依赖激酶的方式负调控TGFβ信号通路,机制上可能与促进Smad4的泛素化修饰,降低Smad4(?)勺稳定性有关,但其生物学意义尚有待深入研究。
This essay includes two parts, the first is hydroxyphenylpyruvate dioxygenase (HPD) up-regulates NF-κB signaling pathway and promotes the survival and migra-tion of lung cancer cell, the second is NLK inhibits TGF-β signaling pathway by interacting with Smad4.
It is said that birds of a feather flock together. The principle is also applicable in biology study. Therefore, Finding out the proteins that interact with your interested protein is an important approach to discover its function. Using yeast two-hybrid system, our lab built large scale protein-protein interaction network which included many newly found protein-protein interactions. The interaction network provides a lot of useful information to us. Two pairs of protein-protein interactions discovered by the network that we believed having important function was further studied. The two interactions are that between HPD and NEMO and that between NLK and Smad4.
HPD is the key enzyme of tyrosine catabolism pathway. NEMO is the core protein that involves in NF-κB signaling pathway. Using in vitro and in vivo coimmunoprecipitation assay, we confirmed the interaction between HPD and NEMO through their N terminals, and HPD may form a protein complex with IKK complex. Ectopic expression of HPD accelerated the degradation of IκBα, enhanced the activity of NF-κB reporter and increased the expression of NF-κB target gene induced by TNFα, including BCL-xL, cIAP2, ICAM-1, VCAM-1; knock down of HPD inhibited the activity of NF-κB reporter; lacking of the enzyme activity of HPD didn't influence its function in up-regulating NF-κB pathway, hydroxyphenylpyruvic acid(HPP), the substrate of HPD, and homogentisic acid(HGA), the product of HPD, had little influence on NF-κB pathway. These results indicate HPD up-regulates NF-κB pathway independent of its enzyme activity. We found over-expression of HPD augments the ubiquitination of NEMO stimulated by TNFα. RT-PCR was used to test the expression of HPD in various organs of mice, the result showed that HPD express in liver and kidney, which is consistent with previous report. Intriguingly, besides the cell lines originated from liver, HPD was detected in many lung cancer cell lines. In order to understand the relationship between HPD and NF-κB signaling pathway in lung cancer, we compared the expression of HPD and phosphorylated p65(S276) in the lung tumor tissue and relative normal lung tissue of lung cancer patients, and found lung tumor tissue expressed higher level of HPD than normal lung tissue, the expression of HPD correlate with that of phosphorylated p65(S276). Subsequently, using lentivirus system, knock-down of HPD inhibited the colonic formation ability and migration of H1299and A549and had no influence on the cell cycle and proliferation of H1299and A549. To sum up, our data show lung cancer tissue express HPD, knock-down of HPD alleviate the malignant phenotype of lung cancer, these effects maybe relevant to the interaction between HPD and NEMO and thereby activation of NF-κB pathway. These results indicated HPD may play important role in the initiation and development of lung cancer.
NLK is a conserved S/T protein kinase, recognizes S/TP motif of the target proteins, involves in many biology process through phosphorylating its target proteins. The result from CoIP and GST-pull down showed that NLK interact with Smad4. NLK down-regulate TGFβ pathway independent of its kinase activity through enhancing the ubiquitination of Smad4and decrease the stability of Smad4. The biological significance of the interaction between NLK and Smad4requires further study.
引文
[1]Wang, J., K. Huo, L. Ma, et al., Toward an understanding of the protein interaction network of the human liver. Mol Syst Biol,2011.7:p.536.
[2]Moran, G.R.,4-Hydroxyphenylpyruvate dioxygenase. Arch Biochem Biophys,2005. 433(1):p.117-28.
[3]Nelson, D.L., NEMO, NFkappaB signaling and incontinentia pigmenti. Curr Opin Genet Dev,2006.16(3):p.282-8.
[4]Fellman, J.H., T.S. Fujita and E.S. Roth, Assay, properties and tissue distribution of p-hydroxyphenylpyruvate hydroxylase. Biochim Biophys Acta,1972.284(1):p.90-100.
[5]Kim, S., Y. Kim, J. Lee, et al., Regulation of FOXO1 by TAK1-Nemo-like kinase pathway. J Biol Chem,2010.285(11):p.8122-9.
[6]Emami, K.H., L.G. Brown, T.E. Pitts, et al., Nemo-like kinase induces apoptosis and inhibits androgen receptor signaling in prostate cancer cells. Prostate,2009.69(14): p.1481-92.
[7]Satoh, K., J. Ohnishi, A. Sato, et al., Nemo-like kinase-myocyte enhancer factor 2A signaling regulates anterior formation in Xenopus development. Mol Cell Biol,2007. 27(21):p.7623-30.
[8]Rottinger, E., J. Croce, G. Lhomond, et al., Nemo-like kinase (NLK) acts downstream of Notch/Delta signalling to downregulate TCF during mesoderm induction in the sea urchin embryo. Development,2006.133(21):p.4341-53.
[9]Yamada, M., J. Ohnishi, B. Ohkawara, et al., NARF, an nemo-like kinase (NLK)-associated ring finger protein regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF). J Biol Chem,2006.281(30):p.20749-60.
[10]Celebrating 25 years of NF-kappaB. Nat Immunol,2011.12(8):p.681.
[11]Warren, R. and S. Beck, Celebrating 25 years of service to oncologists. Oncology (Williston Park),2011.25(5):p.394.
[12]Razani, B., A.D. Reichardt and G. Cheng, Non-canonical NF-kappaB signaling activation and regulation:principles and perspectives. Immunol Rev,2011.244(1):p. 44-54.
[13]Ruan, Q. and Y.H. Chen, Nuclear factor-kappaB in immunity and inflammation:the Treg and Th17 connection. Adv Exp Med Biol,2012.946:p.207-21.
[14]Silke, J., The regulation of TNF signalling:what a tangled web we weave. Curr Opin Immunol,2011.23(5):p.620-6.
[15]Smale, S.T., Hierarchies of NF-kappaB target-gene regulation. Nat Immunol,2011. 12(8):p.689-94.
[16]Cheng, J., A. Montecalvo and L.P. Kane, Regulation of NF-kappaB induction by TCR/CD28. Immunol Res,2011.50(2-3):p.113-7.
[17]Gordon, J.W., J.A. Shaw and L.A. Kirshenbaum, Multiple facets of NF-kappaB in the heart:to be or not to NF-kappaB. Circ Res,2011.108(9):p.1122-32.
[18]Hayden, M.S. and S. Ghosh, NF-kappaB, the first quarter-century:remarkable progress and outstanding questions. Genes Dev,2012.26(3):p.203-34.
[19]Savkovic, S.D., A. Koutsouris and G. Hecht, Activation of NF-kappaB in intestinal epithelial cells by enteropathogenic Escherichia coli. Am J Physiol,1997.273(4 Pt 1): p. C1160-7.
[20]Sen, R. and D. Baltimore, Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell,1986.47(6):p.921-8.
[21]Bachelerie, F., J. Alcami, F. Arenzana-Seisdedos, et al., HIV enhancer activity perpetuated by NF-kappa B induction on infection of monocytes. Nature,1991. 350(6320):p.709-12.
[22]Twu, J.S., K. Chu and W.S. Robinson, Hepatitis B virus X gene activates kappa B-like enhancer sequences in the long terminal repeat of human immunodeficiency virus 1. Proc Natl Acad Sci U S A,1989.86(13):p.5168-72.
[23]Osborn, L., S. Kunkel and G.J. Nabel, Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A,1989.86(7):p.2336-40.
[24]Shea, L.M., C. Beehler, M. Schwartz, et al., Hyperoxia activates NF-kappaB and increases TNF-alpha and IFN-gamma gene expression in mouse pulmonary lymphocytes. J Immunol,1996.157(9):p.3902-8.
[25]Rupec, R.A. and P.A. Baeuerle, The genomic response of tumor cells to hypoxia and reoxygenation. Differential activation of transcription factors AP-1 and NF-kappa B. Eur J Biochem,1995.234(2):p.632-40.
[26]Mori, N. and D. Prager, Transactivation of the interleukin-lalpha promoter by human T-cell leukemia virus type Ⅰ and type Ⅱ Tax proteins. Blood,1996.87(8):p.3410-7.
[27]Serf ling, E., R. Barthelmas, I. Pfeuffer, et al., Ubiquitous and lymphocyte-specific factors are involved in the induction of the mouse interleukin 2 gene in T lymphocytes. EMBO J,1989.8(2):p.465-73.
[28]Libermann, T.A. and D. Baltimore, Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol,1990.10(5):p.2327-34.
[29]Murphy, T.L., M.G. Cleveland, P. Kulesza, et al., Regulation of interleukin 12 p40 expression through an NF-kappa B half-site. Mol Cell Biol,1995.15(10):p.5258-67.
[30]Shakhov, A.N., M.A. Collart, P. Vassalli, et al., Kappa B-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor alpha gene in primary macrophages. J Exp Med,1990.171(1):p.35-47.
[21]Kunsch, C. and C.A. Rosen, NF-kappa B sub unit-specific regulation of the interleukin-8 promoter. Mol Cell Biol,1993.13(10):p.6137-46.
[32]Grove, M. and M. Plumb, C/EBP, NF-kappa B, and c-Ets family members and transcriptional regulation of the cell-specific and inducible macrophage inflammatory protein 1 alpha immediate-early gene. Mol Cell Biol,1993.13(9):p. 5276-89.
[33]lademarco, M.F., J.J. McQuillan, G.D. Rosen, et al., Characterization of the promoter for vascular cell adhesion molecule-1 (VCAM-1). J Biol Chem,1992.267(23):p. 16323-9.
[34]Lenardo, M.J. and D. Baltimore, NF-kappa B:a pleiotropic mediator of inducible and tissue-specific gene control. Cell,1989.58(2):p.227-9.
[35]Malter, J.S. and M.A. Gerber, Regulation of hepatocyte gene expression:progress on the horizon. Hepatology,1989.10(6):p.1017-8.
[36]Baeuerle, P.A., The inducible transcription activator NF-kappa B:regulation by distinct protein subunits. Biochim Biophys Acta,1991.1072(1):p.63-80.
[37]Siebenlist, U., G. Franzoso and K. Brown, Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol,1994.10:p.405-55.
[38]Finco, T.S. and A.S. Baldwin, Mechanistic aspects of NF-kappa B regulation:the emerging role of phosphorylation and proteolysis. Immunity,1995.3(3):p.263-72.
[39]Schmitz, M.L. and P.A. Baeuerle, Multi-step activation of NF-kappa B/Rel transcription factors. Immunobiology,1995.193(2-4):p.116-27.
[40]Thanos, D. and T. Maniatis, NF-kappa B:a lesson in family values. Cell,1995.80(4):p. 529-32.
[41]Kitamura, M., Control of NF-kappaB and inflammation by the unfolded protein response. Int Rev Immunol,2011.30(1):p.4-15.
[42]Defee, M.R., Z. Qin, L. Dai, et al., Extracellular Hsp90 serves as a co-factor for NF-kappaB activation and cellular pathogenesis induced by an oncogenic herpesvirus. Am J Cancer Res,2011.1(5):p.687-700.
[43]Staudt, L.M., Oncogenic activation of NF-kappaB. Cold Spring Harb Perspect Biol, 2010.2(6):p. a000109.
[44]Iha, H., K.V. Kibler, V.R. Yedavalli, et al., Segregation of NF-kappaB activation through NEMO/IKKgamma by Tax and TNFalpha:implications for stimulus-specific interruption of oncogenic signaling. Oncogene,2003.22(55):p.8912-23.
[45]Mayo, M.W., C.Y. Wang, P.C. Cogswell, et al., Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science,1997. 278(5344):p.1812-5.
[46]Galang, C.K., J. Garcia-Ramirez, P.A. Solski, et al., Oncogenic Neu/ErbB-2 increases ets, AP-1, and NF-kappaB-dependent gene expression, and inhibiting ets activation blocks Neu-mediated cellular transformation. J Biol Chem,1996.271(14):p.7992-8.
[47]Wajant, H. and P. Scheurich, TNFR1-induced activation of the classical NF-kappaB pathway. FEBS J,2011.278(6):p.862-76.
[48]Arkan, M.C. and F.R. Greten, IKK-and NF-kappaB-mediated functions in carcinogenesis. Curr Top Microbiol Immunol,2011.349:p.159-69.
[49]Israel, A., The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb Perspect Biol,2010.2(3):p. a000158.
[50]Courtois, G. and A. Israel, IKK regulation and human genetics. Curr Top Microbiol Immunol,2011.349:p.73-95.
[51]Wuerzberger-Davis, S.M. and S. Miyamoto, TAK-ling IKK activation:"Ub" the judge. Sci Signal,2010.3(105):p. pe3.
[52]Shinohara, H., T. Yasuda, Y. Aiba, et al., PKC beta regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1. J Exp Med, 2005.202(10):p.1423-31.
[53]Romashkova, J.A. and S.S. Makarov, NF-kappaB is a target of AKT in anti-apoptotic PDGFsignalling. Nature,1999.401(6748):p.86-90.
[54]Kane, L.P., V.S. Shapiro, D. Stokoe, et al., Induction of NF-kappaB by the Akt/PKB kinase. Curr Biol,1999.9(11):p.601-4.
[55]Arun, P., M.S. Brown, R. Ehsanian, et al., Nuclear NF-kappaB p65 phosphorylation at serine 276 by protein kinase A contributes to the malignant phenotype of head and neck cancer. Clin Cancer Res,2009.15(19):p.5974-84.
[56]Sizemore, N., S. Leung and G.R. Stark, Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-kappaB p65/RelA subunit. Mol Cell Biol,1999.19(7):p.4798-805.
[57]Madrid, L.V., C.Y. Wang, D.C. Guttridge, et al., Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-kappaB. Mol Cell Biol,2000.20(5):p.1626-38.
[58]Vermeulen, L., G. De Wilde, P. Van Damme, et al., Transcriptional activation of the NF-kappaB p65 subunit by mitogen-and stress-activated protein kinase-1 (MSK1). EMBO J,2003.22(6):p.1313-24.
[59]Le Page, C., I.H. Koumakpayi, L. Lessard, et al., Independent role of phosphoinositol-3-kinase (PI3K) and casein kinase Ⅱ (CK-2) in EGFR and Her-2-mediated constitutive NF-kappaB activation in prostate cancer cells. Prostate,2005.65(4):p.306-15.
[60]Ten, R.M., C.V. Paya, N. Israel, et al., The characterization of the promoter of the gene encoding the p50 subunit of NF-kappa B indicates that it participates in its own regulation. EMBO J,1992.11(1):p.195-203.
[61]Kanarek, N., N. London, O. Schueler-Furman, et al., Ubiquitination and degradation of the inhibitors of NF-kappaB. Cold Spring Harb Perspect Biol,2010.2(2):p. a000166.
[62]Traenckner, E.B., H.L. Pahl, T. Henkel, et al., Phosphorylation of human I kappa B-alpha on serines 32 and 36 controls I kappa B-alpha proteolysis and NF-kappa B activation in response to diverse stimuli. EMBO J,1995.14(12):p.2876-83.
[63]Tashiro, K., M.P. Pando, Y. Kanegae, et al., Direct involvement of the ubiquitin-conjugating enzyme Ubc9/Hus5 in the degradation of IkappaBalpha. Proc Natl Acad Sci U S A,1997.94(15):p.7862-7.
[64]Kaltschmidt, B., P.A. Baeuerle and C. Kaltschmidt, Potential involvement of the transcription factor NF-kappa B in neurological disorders. Mol Aspects Med,1993. 14(3):p.171-90.
[65]Peltz, G., Transcription factors in immune-mediated disease. Curr Opin Biotechnol, 1997.8(4):p.467-73.
[66]Guijarro, C. and J. Egido, Transcription factor-kappa B (NF-kappa B) and renal disease. Kidney Int,2001.59(2):p.415-24.
[67]Tak, P.P. and G.S. Firestein, NF-kappaB:a key role in inflammatory diseases. J Clin Invest,2001.107(1):p.7-11.
[68]Baldwin, A.S., Jr., Series introduction:the transcription factor NF-kappaB and human disease. J Clin Invest,2001.107(1):p.3-6.
[69]Regnier, C.H., H.Y. Song, X. Gao, et al., Identification and characterization of an IkappaB kinase. Cell,1997.90(2):p.373-83.
[70]DiDonato, J.A., M. Hayakawa, D.M. Rothwarf, et al., A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature,1997.388(6642):p. 548-54.
[71]Mercurio, F., H. Zhu, B.W. Murray, et al., IKK-1 and IKK-2:cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science,1997.278(5339):p.860-6.
[72]Woronicz, J.D., X. Gao, Z. Cao, et al., IkappaB kinase-beta:NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science,1997.278(5339):p. 866-9.
[73]Zhao, J., E. Hoye, S. Boylan, et al., Quaternary structures of a catalytic subunit-regulatory subunit dimeric complex and the holoenzyme of the cAMF-dependent protein kinase by neutron contrast variation. J Biol Chem,1998.273(46):p.30448-59.
[74]Rothwarf, D.M., E. Zandi, G. Natoli, et al., IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature,1998.395(6699):p.297-300.
[75]Maniatis, T., A ubiquitin ligase complex essential for the NF-kappaB, Wnt/Wingless, and Hedgehog signaling pathways. Genes Dev,1999.13(5):p.505-10.
[76]Karin, M. and Y. Ben-Neriah, Phosphorylation meets ubiquitination:the control of NF-[kappa]B activity. Annu Rev Immunol,2000.18:p.621-63.
[77]Chen, Z.J., Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol,2005.7(8):p. 758-65.
[78]Ravid, T. and M. Hochstrasser, NF-kappaB signaling:flipping the switch with polyubiquitin chains. Curr Biol,20,04.14(23):p. R898-900.
[79]Chiu, Y.H., M. Zhao and Z.J. Chen, Ubiquitin in NF-kappaB signaling. Chem Rev,2009. 109(4):p.1549-60.
[80]Israel, A., NF-kappaB activation:Nondegradative ubiquitination implicates NEMO. Trends Immunol,2006.27(9):p.395-7.
[81]Wu, C.J., D.B. Conze, T. Li, et al., Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected]. Nat Cell Biol,2006.8(4):p.398-406.
[82]Sun, L, L. Deng, C.K. Ea, et al., The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell,2004.14(3):p.289-301.
[83]Abbott, D.W., Y. Yang, J.E. Hutti, et al., Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains. Mol Cell Biol,2007.27(17):p. 6012-25.
[84]Boland, M.P., DNA damage signalling and NF-kappaB:implications for survival and death in mammalian cells. Biochem Soc Trans,2001.29(Pt 6):p.674-8.
[85]Zhou, H., I. Wertz, K. O'Rourke, et al., Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature,2004.427(6970):p.167-71.
[86]Oeckinghaus, A., E. Wegener, V. Welteke, et al., Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation. EMBO J,2007.26(22):p.4634-45.
[87]Kovalenko, A., C. Chable-Bessia, G. Cantarella, et al., The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature,2003. 424(6950):p.801-5.
[88]Brummelkamp, T.R., S.M. Nijman, A.M. Dirac, et al., Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature,2003. 424(6950):p.797-801.
[89]Wertz, I.E., K.M. O'Rourke, H. Zhou, et al., De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature,2004.430(7000):p. 694-9.
[90]Mauro, C., F. Pacifico, A. Lavorgna, et al., ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB. J Biol Chem,2006.281(27):p.18482-8.
[91]Grilli, M. and M. Memo, Possible role of NF-kappaB and p53 in the glutamate-induced pro-apoptotic neuronal pathway. Cell Death Differ,1999.6(1):p.22-7.
[92]Rocha, S. and N.D. Perkins, ARF the integrator:linking NF-kappaB, p53 and checkpoint kinases. Cell Cycle,2005.4(6):p.756-9.
[93]Karin, M., The NF-kappa B activation pathway:its regulation and role in inflammation and cell survival. Cancer J Sci Am,1998.4 Suppl 1:p. S92-9.
[94]Jones, P.L., D. Ping and J.M. Boss, Tumor necrosis factor alpha and interleukin-1beta regulate the murine manganese superoxide dismutase gene through a complex intronic enhancer involving C/EBP-beta and NF-kappaB. Mol Cell Biol,1997.17(12):p. 6970-81.
[95]Joyce, D., C. Albanese, J. Steer, et al., NF-kappaB and cell-cycle regulation:the cyclin connection. Cytokine Growth Factor Rev,2001.12(1):p.73-90.
[96]Pidgeon, G.P., J.H. Harmey, E. Kay, et al., The role of endotoxin/lipopolysaccharide in surgically induced tumour growth in a murine model of metastatic disease. Br J Cancer,1999.81(8):p.1311-7.
[97]Greten, F.R., L. Eckmann, T.F. Greten, et al., IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell,2004.118(3):p. 285-96.
[98]Luo, J.L., H. Kamata and M. Karin, IKK/NF-kappaB signaling:balancing life and death--a new approach to cancer therapy. J Clin Invest,2005.115(10):p.2625-32.
[99]Potter, J.D. and C.M. Ulrich, COX-2 and gastric cancer:More on inflammation and neoplasia. Gastroenterology,2006.130(7):p.2198-200.
[100]Hahm, K.B., H.Y. Lim, S. Sohn, et al., In vitro evidence of the role of COX-2 in attenuating gastric inflammation and promoting gastric carcinogenesis. J Environ Pathol Toxicol Oncol,2002.21(2):p.165-76.
[101]Pikarsky, E., R.M. Porat, I. Stein, et al., NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature,2004.431(7007):p.461-6.
[102]Feng, X.H. and R. Derynck, Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol,2005.21:p.659-93.
[103]Derynck, R. and Y.E. Zhang, Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature,2003.425(6958):p.577-84.
[104]Massague, J., TGFbeta in Cancer. Cell,2008.134(2):p.215-30.
[105]Petrocca, F., R. Visone, M.R. Onelli, et al., E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell, 2008.13(3):p.272-86.
[106]Massague, J., How cells read TGF-beta signals. Nat Rev Mol Cell Biol,2000.1(3):p. 169-78.
[107]Itoh, S., F. Itoh, M.J. Goumans, et al., Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem,2000.267(24):p.6954-67.
[108]Moustakas, A., S. Souchelnytskyi and C.H. Heldin, Smad regulation in TGF-beta signal transduction. J Cell Sci,2001.114(Pt 24):p.4359-69.
[109]Gentry, L.E., M.N. Lioubin, A.F. Purchio, et al., Molecular events in the processing of recombinant type 1 pre-pro-transforming growth factor beta to the mature polypeptide. Mol Cell Biol,1988.8(10):p.4162-8.
[110]Derynck, R., J.A. Jarrett, E.Y. Chen, et al., Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature,1985.316(6030):p.701-5.
[111]Gentry, L.E., N.R. Webb, G.J. Lim, et al., Type 1 transforming growth factor beta: amplified expression and secretion of mature and precursor polypeptides in Chinese hamster ovary cells. Mol Cell Biol,1987.7(10):p.3418-27.
[112]Miyazono, K., H. Ichijo and C.H. Heldin, Transforming growth factor-beta:latent forms, binding proteins and receptors. Growth Factors,1993.8(1):p.11-22.
[113]Taipale, J., K. Miyazono, C.H. Heldin, et al., Latent transforming growth factor-beta 1 associates to fibroblast extracellular matrix via latent TGF-beta binding protein. J Cell Biol,1994.124(1-2):p.171-81.
[114]Nunes, I., P.E. Gleizes, C.N. Metz, et al., Latent transforming growth factor-beta binding protein domains involved in activation and transglutaminase-dependent cross-linking of latent transforming growth factor-beta. J Cell Biol,1997.136(5):p. 1151-63.
[115]Ueno, N., N. Ling, S.Y. Ying, et al., Isolation and partial characterization of follistatin: a single-chain Mr 35,000 monomeric protein that inhibits the release of follicle-stimulating hormone. Proc Natl Acad Sci U S A,1987.84(23):p.8282-6.
[116]de Winter, J.P., P. ten Dijke, C.J. de Vries, et al., Follistatins neutralize activin bioactivity by inhibition of activin binding to its type Ⅱ receptors. Mol Cell Endocrinol, 1996.116(1):p.105-14.
[117]Zimmerman, L.B., J.M. De Jesus-Escobar and R.M. Harland, The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell,1996.86(4): p.599-606.
[118]Piccolo, S., Y. Sasai, B. Lu, et al., Dorsoventral patterning in Xenopus:inhibition of ventral signals by direct binding of chordin to BMP-4. Cell,1996.86(4):p.589-98.
[119]Kretzschmar, M., J. Doody, I. Timokhina, et al., A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev,1999.13(7):p.804-16.
[120]Engel, M.E., M.A. McDonnell, B.K. Law, et al., Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription. J Biol Chem, 1999.274(52):p.37413-20.
[121]Wicks, S.J., S. Lui, N. Abdel-Wahab, et al., Inactivation of smad-transforming growth factor beta signaling by Ca(2+)-calmodulin-dependent protein kinase II. Mol Cell Biol, 2000.20(21):p.8103-11.
[122]Arora, K. and R. Warrior, A new Smurf in the village. Dev Cell,2001.1(4):p.441-2.
[123]Zhu, H., P. Kavsak, S. Abdollah, et al., A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature,1999.400(6745):p.687-93.
[124]Zhang, Y., C. Chang, D.J. Gehling, et al., Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc Natl Acad Sci U S A,2001.98(3):p.974;9.
[125]Inman, G.J., F.J. Nicolas and C.S. Hill, Nucleocytoplasmic shuttling of Smads 2,3, and 4 permits sensing of TGF-beta receptor activity. Mol Cell,2002.10(2):p.283-94.
[126]Watanabe, M., N. Masuyama, M. Fukuda, et al., Regulation of intracellular dynamics of Smad4 by its leucine-rich nuclear export signal. EMBO Rep,2000.1(2):p.176-82.
[127]Xiao, Z., N. Watson, C. Rodriguez, et al., Nucleocytoplasmic shuttling of Smadl conferred by its nuclear localization and nuclear export signals. J Biol Chem,2001. 276(42):p.39404-10.
[128]Xu, L., Y.G. Chen and J. Massague, The nuclear import function of Smad2 is masked by SARA and unmasked by TGFbeta-dependent phosphorylation. Nat Cell Biol,2000. 2(8):p.559-62.
[129]Kurisaki, A., S. Kose, Y. Yoneda, et al., Transforming growth factor-beta induces nuclear import of Smad3 in an importin-betal and Ran-dependent manner. Mol Biol Cell,2001.12(4):p.1079-91.
[130]Xu, L., Y. Kang, S. Col, et al., Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFbeta signaling complexes in the cytoplasm and nucleus. Mol Cell,2002.10(2):p.271-82.
[131]Akhurst, R.J. and R. Derynck, TGF-beta signaling in cancer--a double-edged sword. Trends Cell Biol,2001.11(11):p. S44-51.
[132]Shi, Y., Y.F. Wang, L. Jayaraman, et al., Crystal structure of a Smad MH1 domain bound to DNA:insights on DNA binding in TGF-beta signaling. Cell,1998.94(5):p. 585-94.
[133]Derynck, R., Y. Zhang and X.H. Feng, Smads:transcriptional activators of TGF-beta responses. Cell,1998.95(6):p.737-40.
[134]Germain, S., M. Howell, G.M. Esslemont, et al., Homeodomain and winged-helix transcription factors recruit activated Smads to distinct promoter elements via a common Smad interaction motif. Genes Dev,2000.14(4):p.435-51.
[135]Luo, K., S.L. Stroschein, W. Wang, et al., The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling. Genes Dev,1999.13(17):p.2196-206.
[136]Sun, Y., X. Liu, E. Ng-Eaton, et al., SnoN and Ski protooncoproteins are rapidly degraded in response to transforming growth factor beta signaling. Proc Natl Acad Sci U S A,1999.96(22):p.12442-7.
[137]Wotton, D., R.S. Lo, S. Lee, et al., A Smad transcriptional corepressor. Cell,1999. 97(1):p.29-39.
[138]Feng, X.H., Y. Zhang, R.Y. Wu, et al., The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation. Genes Dev,1998.12(14):p.2153-63.
[139]Wang, G., J. Long, I. Matsuura, et al., The Smad3 linker region contains a transcriptional activation domain. Biochem J,2005.386(Pt 1):p.29-34.
[140]Kim, R.H., D. Wang, M. Tsang, et al., A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction. Genes Dev,2000.14(13): p.1605-16.
[141]Endo, F., S. Kubo, H. Awata, et al., Complete rescue of lethal albino d4CoS mice by null mutation of 4-hydroxyphenylpyruvate dioxygenase and induction of apoptosis of hepatocytes in these mice by in vivo retrieval of the tyrosine catabolic pathway. J Biol Chem,1997.272(39):p.24426-32.
[142]Endo, F., H. Katoh, S. Yamamoto, et al., A murine model for type Ⅲ tyrosinemia:lack of immunologically detectable 4-hydroxyphenylpyruvic acid dioxygenase enzyme protein in a novel mouse strain with hypertyrosinemia. Am J Hum Genet,1991.48(4): p.704-9.
[143]Hager, S.E., R.I. Gregerman and W.E. Knox, p-Hydroxyphenylpyruvate oxidase of liver. J Biol Chem,1957.225(2):p.935-47.
[144]Nakai, C., M. Nozaki and O. Hayaishi, Studies on a possible reaction intermediate of p-hydroxyphenylpyruvate dioxygenase. Biochem Biophys Res Commun,1975.67(2): p.590-5.
[145]Borowski, T., A. Bassan and P.E. Siegbahn,4-Hydroxyphenylpyruvate dioxygenase:a hybrid density functional study of the catalytic reaction mechanism. Biochemistry, 2004.43(38):p.12331-42.
[146]Neve, S., L. Aarenstrup, D. Tornehave, et al., Tissue distribution, intracellular localization and proteolytic processing of rat 4-hydroxyphenylpyruvate dioxygenase. Cell Biol Int,2003.27(8):p.611-24.
[147]Lee, M.H., Z.H. Zhang, C.H. MacKinnon, et al., The C-terminal of rat 4-hydroxyphenylpyruvate dioxygenase is indispensable for enzyme activity. FEBS Lett, 1996.393(2-3):p.269-72.
[148]Wong, K.K., T. Jacks and G. Dranoff, NF-kappaB fans the flames of lung carcinogenesis. Cancer Prev Res (Phila),2010.3(4):p.403-5.
[149]Hanahan, D. and R.A. Weinberg, Hallmarks of cancer:the next generation. Cell,2011. 144(5):p.646-74.
[150]Chen, F., Y. Lu, Z. Zhang, et al., Opposite effect of NF-kappa B and c-Jun N-terminal kinase on p53-independent GADD45 induction by arsenite. J Biol Chem,2001. 276(14):p.11414-9.
[151]Karin, M. and A. Lin, NF-kappaB at the crossroads of life and death. Nat Immunol, 2002.3(3):p.221-7.
[152]Ju, W., X. Wang, H. Shi, et al., A critical role of luteolin-induced reactive oxygen species in blockage of tumor necrosis factor-activated nuclear factor-kappaB pathway and sensitization of apoptosis in lung cancer cells. Mol Pharmacol,2007. 71(5):p.1381-8.
[153]Kim, K.M. and Y.J. Lee, Amiloride augments TRAIL-induced apoptotic death by inhibiting phosphorylation of kinases and phosphatases associated with the P13K-Akt pathway. Oncogene,2005.24(3):p.355-66.
[154]Lin, Y., L. Bai, W. Chen, et al., The NF-kappaB activation pathways, emerging molecular targets for cancer prevention and therapy. Expert Opin Ther Targets,2010. 14(1):p.45-55.
[155]Wang, X. and Y. Lin, Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacol Sin,2008.29(11):p.1275-88.
[156]Grivennikov, S.I., F.R. Greten and M. Karin, Immunity, inflammation, and cancer. Cell, 2010.140(6):p.883-99.
[157]Abbott, D.W., A. Wilkins, J.M. Asara, et al., The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr Biol, 2004.14(24):p.2217-27.
[158]Warburg, O., On respiratory impairment in cancer cells. Science,1956.124(3215):p. 269-70.
[159]Warburg, O., On the origin of cancer cells. Science,1956.123(3191):p.309-14.
[160]Vander Heiden, M.G., L.C. Cantley and C.B. Thompson, Understanding the Warburg effect:the metabolic requirements of cell proliferation. Science,2009.324(5930):p. 1029-33.
[161]Kawauchi, K., K. Araki, K. Tobiume, et al., p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nat Cell Biol,2008. 10(5):p.611-8.
[162]Morgan, M.J. and Z.G. Liu, Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res,2011.21(1):p.103-15.
[163]Villanueva, A., C. Garcia, A.B. Paules, et al., Disruption of the antiproliferative TGF-beta signaling pathways in human pancreatic cancer cells. Oncogene,1998.17(15): p.1969-78.
[164]Tang, B., E.P. Bottinger, S.B. Jakowlew, et al., Transforming growth factor-betal is a new form of tumor suppressor with true haploid insufficiency. Nat Med,1998.4(7):p. 802-7.
[165]Mukhopadhyay, T., J.A. Roth and S.A. Maxwell, Altered expression of the p50 subunit of the NF-kappa B transcription factor complex in non-small cell lung carcinoma. Oncogene,1995.11(5):p.999-1003.
[166]Pietenpol, J.A., R.W. Stein, E. Moran, et al., TGF-beta 1 inhibition of c-myc transcription and growth in keratinocytes is abrogated by viral transforming proteins with pRB binding domains. Cell,1990.61(5):p.777-85.
[167]Polyak, K., J.Y. Kato, M.J. Solomon, et al., p27Kipl, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev,1994.8(1):p.9-22.
[168]. Alexandrow, M.G. and H.L. Moses, Transforming growth factor beta and cell cycle regulation. Cancer Res,1995.55(7):p.1452-7.
[169]Wang, X., W. Ju, J. Renouard, et al.,17-allylamino-17-demethoxygeldanamycin synergistically potentiates tumor necrosis factor-induced lung cancer cell death by blocking the nuclear factor-kappaB pathway. Cancer Res,2006.66(2):p.1089-95.
[170]Datto, M.B., Y. Li, J.F. Panus, et al., Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci U S A,1995.92(12):p.5545-9.
[171]Markowitz, S.D. and A.B. Roberts, Tumor suppressor activity of the TGF-beta pathway in human cancers. Cytokine Growth Factor Rev,1996.7(1):p.93-102.
[172]Barbie, D.A., P. Tamayo, J.S. Boehm, et al., Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature,2009.462(7269):p.108-12.
[173]Ishitani, T., J. Ninomiya-Tsuji, S. Nagai, et al., The TAKl-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. Nature, 1999.399(6738):p.798-802.
[174]Takada, I., M. Mihara, M. Suzawa, et al., A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat Cell Biol,2007.9(11):p.1273-85.
[175]Kortenjann, M., M. Nehls, A.J. Smith, et al., Abnormal bone marrow stroma in mice deficient for nemo-like kinase, Nlk. Eur J Immunol,2001.31(12):p.3580-7.
[176]Kojima, H., T. Sasaki, T. Ishitani, et al., STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFbeta-activated kinase 1 for STAT3 Ser-727 phosphorylation. Proc Natl Acad Sci U S A,2005.102(12):p.4524-9.
[177]Labbe, E., A. Letamendia and L. Attisano, Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-beta and wnt pathways. Proc Natl Acad Sci U S A,2000. 97(15):p.8358-63.
[178]Yasuda, J., H. Yokoo, T. Yamada, et al., Nemo-like kinase suppresses a wide range of transcription factors, including nuclear factor-kappaB. Cancer Sci,2004.95(1):p.52-7.
[179]Ehrlich, M., D. Horbelt, B. Marom, et al., Homomeric and heteromeric complexes among TGF-beta and BMP receptors and their roles in signaling. Cell Signal,2011. 23(9):p.1424-32.
[180]Lan, H.Y. and A.C. Chung, Transforming growth factor-beta and Smads. Contrib Nephrol,2011.170:p.75-82.
[181]Ishitani, T., J. Ninomiya-Tsuji and K. Matsumoto, Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related Nemo-like kinase-dependent phosphorylation in Wnt/beta-catenin signaling. Mol Cell Biol,2003.23(4): p.1379-89.
[1]Sen, R. and D. Baltimore, Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell,1986.46(5):p.705-16.
[2]Sen, R. and D. Baltimore, Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell,1986.47(6):p.921-8.
[3]Baeuerle, P.A. and D. Baltimore, A 65-kappaD subunit of active NF-kappaB is required for inhibition of NF-kappaB by I kappaB. Genes Dev,1989.3(11):p.1689-98.
[4]Ghosh, S., A.M. Gifford, L.R. Riviere, et al., Cloning of the p50 DNA binding subunit of NF-kappa B:homology to rel and dorsal. Cell,1990.62(5):p.1019-29.
[5]Kieran, M., V. Blank, F. Logeat, et al., The DNA binding subunit of NF-kappa B is identical to factor KBF1 and homologous to the rel oncogene product. Cell,1990. 62(5):p.1007-18.
[6]Nolan, G.P., S. Ghosh, H.C. Liou, et al., DNA binding and I kappa B inhibition of the cloned p65 subunit of NF-kappa B, a rel-related polypeptide. Cell,1991.64(5):p.961-9.
[7]Ruben, S.M., P.J. Dillon, R. Schreck, et al., Isolation of a rel-related human cDNA that potentially encodes the 65-kD subunit of NF-kappa B. Science,1991.254(5028):p.11.
[8]Neri, A., C.C. Chang, L. Lombardi, et al., B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-kappa B p50. Cell,1991.67(6):p.1075-87.
[9]Hayden, M.S. and S. Ghosh, NF-kappaB, the first quarter-century:remarkable progress and outstanding questions. Genes Dev,2012.26(3):p.203-34.
[10]Haskill, S., A.A. Beg, S.M. Tompkins, et al., Characterization of an immediate-early gene induced in adherent monocytes that encodes I kappa B-like activity. Cell,1991. 65(7):p.1281-9.
[11]Davis, N., S. Ghosh, D.L. Simmons, et al., Rel-associated pp40:an inhibitor of the rel family of transcription factors. Science,1991.253(5025):p.1268-71.
[12]Kerr, L.D., J. Inoue, N. Davis, et al., The rel-associated pp40 protein prevents DNA binding of Rel and NF-kappa B:relationship with I kappa B beta and regulation by phosphorylation. Genes Dev,1991.5(8):p.1464-76.
[13]Thompson, J.E., R.J. Phillips, H. Erdjument-Bromage, et al.,I kappa B-beta regulates the persistent response in a biphasic activation of NF-kappa B. Cell,1995.80(4):p. 573-82.
[14]Wulczyn, F.G., M. Naumann and C. Scheidereit, Candidate proto-oncogene bcl-3 encodes a subunit-specific inhibitor of transcription factor NF-kappa B. Nature,1992. 358(6387):p.597-9.
[15]Yamazaki, S., T. Muta and K. Takeshige, A novel IkappaB protein, IkappaB-zeta, induced by proinflammatory stimuli, negatively regulates nuclear factor-kappaB in the nuclei. J Biol Chem,2001.276(29):p.27657-62.
[16]Henkel, T., T. Machleidt, I. Alkalay, et al., Rapid proteolysis of I kappa B-alpha is necessary for activation of transcription factor NF-kappa B. Nature,1993.365(6442): p.182-5.
[17]Alkalay, I., A. Yaron, A. Hatzubai, et al., Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A,1995.92(23):p.10599-603.
[18]Chen, Z., J. Hagler, V.J. Palombella, et al., Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev,1995. 9(13):p.1586-97.
[19]Regnier, C.H., H.Y. Song, X. Gao, et al., Identification and characterization of an IkappaB kinase. Cell,1997.90(2):p.373-83.
[20]DiDonato, J.A., M. Hayakawa, D.M. Rothwarf, et al., A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature,1997.388(6642):p. 548-54.
[21]Zandi, E., D.M. Rothwarf, M. Delhase, et al., The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell,1997.91(2):p.243-52.
[22]Mercurio, F., H. Zhu, B.W. Murray, et al., IKK-1 and IKK-2:cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science,1997.278(5339):p.860-6.
[23]Woronicz, J.D., X. Gao, Z. Cao, et al., IkappaB kinase-beta:NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science,1997.278(5339):p. 866-9.
[24]Yamaoka, S., G. Courtois, C. Bessia, et al., Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell, 1998.93(7):p.1231-40.
[25]Rothwarf, D.M., E. Zandi, G. Natoli, et al., IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature,1998.395(6699):p.297-300.
[26]Tang, E.D., C,Y. Wanr, Y. Xiong, et al., A role for NF-kappaB essential modifier/lkappaB kinase-gamma (NEMO/IKKgamma) ubiquitination in the activation of the IkappaB kinase complex by tumor necrosis factor-alpha. J Biol Chem,2003. 278(39):p.37297-305.
[27]Stilo, R., D. Liguoro, B. Di Jeso, et al., Physical and functional interaction of CARMA1 and CARMA3 with Ikappa kinase gamma-NFkappaB essential modulator. J Biol Chem, 2004.279(33):p.34323-31.
[28]Zhang, S.Q., A. Kovalenko, G. Cantarella, et al., Recruitment of the IKK signalosome to the p55 TNF receptor:RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation. Immunity,2000.12(3):p.301-11.
[29]Wu, C.J. and J.D. Ashwell, NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-kappaB activation. Proc Natl Acad Sci U S A,2008.105(8): p.3023-8.
[30]Cooke, E.L., I.J. Uings, C.L. Xia, et al.. Functional analysis of the interleukin-1-receptor-associated kinase (IRAK-1) in interleukin-1 beta-stimulated nuclear factor kappa B (NF-kappa B) pathway activation:IRAK-1 associates with the NF-kappa B essential modulator (NEMO) upon receptor stimulation. Biochem J,2001.359(Pt 2): p.403-10.
[31]Windheim, M., M. Stafford, M. Peggie, et al., Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase. Mol Cell Biol,2008.28(5):p. 1783-91.
[32]Chariot, A., A. Leonardi, J. Muller, et al., Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases. J Biol Chem,2002.277(40):p.37029-36.
[33]Bonif, M., M.A. Meuwis, P. Close, et al., TNFalpha- and IKKbeta-mediated TANK/I-TRAF phosphorylation:implications for interaction with NEMO/IKKgamma and NF-kappaB activation. Biochem J,2006.394(Pt 3):p.593-603.
[34]Miranda, C., E. Roccato, G. Raho, et al., The TFG protein, involved in oncogenic rearrangements, interacts with TANK and NEMO, two proteins involved in the NF-kappaB pathway. J Cell Physiol,2006.208(1):p.154-60.
[35]Poyet, J.L., S.M. Srinivasula and E.S. Alnemri, vCLAP, a caspase-recruitment domain-containing protein of equine Herpesvirus-2, persistently activates the Ikappa B kinases through oligomerization of IKKgamma. J Biol Chem,2001.276(5):p.3183-7.
[36]Liu, L., M.T. Eby, N. Rathore, et al., The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Ikappa B kinase complex. J Biol Chem,2002.277(16):p.13745-51.
[37]Field, N., W. Low, M. Daniels, et al., KSHV vFLIP binds to IKK-gamma to activate IKK. J Cell Sci,2003.116(Pt 18):p.3721-8.
[38]Shifera, A.S., Proteins that bind to IKKgamma (NEMO) and down-regulate the activation of NF-kappaB. Biochem Biophys Res Commun,2010.396(3):p.585-9.
[39]Lee, E.G., D.L. Boone, S. Chai, et al., Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science,2000.289(5488):p.2350-4.
[40]He, K.L. and A.T. Ting, A20 inhibits tumor necrosis factor (TNF) alpha-induced apoptosis by disrupting recruitment of TRADD and RIP to the TNF receptor 1 complex in Jurkat T cells. Mol Cell Biol,2002.22(17):p.6034-45.
[41]Wertz, I.E., K.M. O'Rourke, H. Zhou, et al., De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature,2004.430(7000):p. 694-9.
[42]Stilo, R., E. Varricchio, D. Liguoro, et al., A20 is a negative regulator of BCL10-and CARMA3-mediated activation of NF-kappaB. J Cell Sci,2008.121(Pt 8):p.1165-71.
[43]Oshima, S., E.E. Turer, J.A. Callahan, et al., ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development. Nature,2009.457(7231):p.906-9.
[44]Wagner, S., I. Carpentier, V. Rogov, et al., Ubiquitin binding mediates the NF-kappaB inhibitory potential of ABIN proteins. Oncogene,2008.27(26):p.3739-45.
[45]Kovalenko, A., C. Chable-Bessia, G. Cantarella, et al., The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature,2003. 424(6950):p.801-5.
[46]Brummelkamp, T.R., S.M. Nijman, A.M. Dirac, et al., Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature,2003. 424(6950):p.797-801.
[47]Reiley, W., M. Zhang, X. Wu, et al., Regulation of the deubiquitinating enzyme CYLD by IkappaB kinase gamma-dependent phosphorylation. Mol Cell Biol,2005.25(10):p. 3886-95.
[48]Ashida, H., M. Kim, M. Schmidt-Supprian, et al., A bacterial E3 ubiquitin ligase lpaH9.8 targets NEMO/IKKgamma to dampen the host NF-kappaB-mediated inflammatory response. Nat Cell Biol,2010.12(1):p.66-73; sup pp 1-9.
[49]Huang, T.T., S.M. Wuerzberger-Davis, Z.H. Wu, et al., Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. Cell,2003.115(5):p.565-76.
[50]Habraken, Y. and J. Piette, NF-kappaB activation by double-strand breaks. Biochem Pharmacol,2006.72(9):p.1132-41.
[51]Janssens, S. and J. Tschopp, Signals from within:the DNA-damage-induced NF-kappaB response. Cell Death Differ,2006.13(5):p.773-84.
[52]Sebban, H., S. Yamaoka and G. Courtois, Posttranslational modifications of NEMO and its partners in NF-kappaB signaling. Trends Cell Biol,2006.16(11):p.569-77.
[53]Janssens, S., A. Tinel, S. Lippens, et al., PIDD mediates NF-kappaB activation in re(?)ponse to DNA damage. Cell,2005.123(6):p.1079-92.
[54]Wu, Z.H., Y. Shi, R.S. Tibbetts, et al., Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli. Science,2006.311(5764):p. 1141-6.
[55]Wuerzberger-Davis, S.M., Y. Nakamura, B.J. Seufzer, et al., NF-kappaB activation by combinations of NEMO SUMOylation and ATM activation stresses in the absence of DNA damage. Oncogene,2007.26(5):p.641-51.
[56]Mabb, A.M., S.M. Wuerzberger-Davis and S. Miyamoto, PIASy mediates NEMO sumoylation and NF-kappaB activation in response to genotoxic stress. Nat Cell Biol, 2006.8(9):p.986-93.
[2]Moran, G.R.,4-Hydroxyphenylpyruvate dioxygenase. Arch Biochem Biophys,2005. 433(1):p.117-28.
[3]Nelson, D.L., NEMO, NFkappaB signaling and incontinentia pigmenti. Curr Opin Genet Dev,2006.16(3):p.282-8.
[4]Fellman, J.H., T.S. Fujita and E.S. Roth, Assay, properties and tissue distribution of p-hydroxyphenylpyruvate hydroxylase. Biochim Biophys Acta,1972.284(1):p.90-100.
[5]Kim, S., Y. Kim, J. Lee, et al., Regulation of FOXO1 by TAK1-Nemo-like kinase pathway. J Biol Chem,2010.285(11):p.8122-9.
[6]Emami, K.H., L.G. Brown, T.E. Pitts, et al., Nemo-like kinase induces apoptosis and inhibits androgen receptor signaling in prostate cancer cells. Prostate,2009.69(14): p.1481-92.
[7]Satoh, K., J. Ohnishi, A. Sato, et al., Nemo-like kinase-myocyte enhancer factor 2A signaling regulates anterior formation in Xenopus development. Mol Cell Biol,2007. 27(21):p.7623-30.
[8]Rottinger, E., J. Croce, G. Lhomond, et al., Nemo-like kinase (NLK) acts downstream of Notch/Delta signalling to downregulate TCF during mesoderm induction in the sea urchin embryo. Development,2006.133(21):p.4341-53.
[9]Yamada, M., J. Ohnishi, B. Ohkawara, et al., NARF, an nemo-like kinase (NLK)-associated ring finger protein regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF). J Biol Chem,2006.281(30):p.20749-60.
[10]Celebrating 25 years of NF-kappaB. Nat Immunol,2011.12(8):p.681.
[11]Warren, R. and S. Beck, Celebrating 25 years of service to oncologists. Oncology (Williston Park),2011.25(5):p.394.
[12]Razani, B., A.D. Reichardt and G. Cheng, Non-canonical NF-kappaB signaling activation and regulation:principles and perspectives. Immunol Rev,2011.244(1):p. 44-54.
[13]Ruan, Q. and Y.H. Chen, Nuclear factor-kappaB in immunity and inflammation:the Treg and Th17 connection. Adv Exp Med Biol,2012.946:p.207-21.
[14]Silke, J., The regulation of TNF signalling:what a tangled web we weave. Curr Opin Immunol,2011.23(5):p.620-6.
[15]Smale, S.T., Hierarchies of NF-kappaB target-gene regulation. Nat Immunol,2011. 12(8):p.689-94.
[16]Cheng, J., A. Montecalvo and L.P. Kane, Regulation of NF-kappaB induction by TCR/CD28. Immunol Res,2011.50(2-3):p.113-7.
[17]Gordon, J.W., J.A. Shaw and L.A. Kirshenbaum, Multiple facets of NF-kappaB in the heart:to be or not to NF-kappaB. Circ Res,2011.108(9):p.1122-32.
[18]Hayden, M.S. and S. Ghosh, NF-kappaB, the first quarter-century:remarkable progress and outstanding questions. Genes Dev,2012.26(3):p.203-34.
[19]Savkovic, S.D., A. Koutsouris and G. Hecht, Activation of NF-kappaB in intestinal epithelial cells by enteropathogenic Escherichia coli. Am J Physiol,1997.273(4 Pt 1): p. C1160-7.
[20]Sen, R. and D. Baltimore, Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell,1986.47(6):p.921-8.
[21]Bachelerie, F., J. Alcami, F. Arenzana-Seisdedos, et al., HIV enhancer activity perpetuated by NF-kappa B induction on infection of monocytes. Nature,1991. 350(6320):p.709-12.
[22]Twu, J.S., K. Chu and W.S. Robinson, Hepatitis B virus X gene activates kappa B-like enhancer sequences in the long terminal repeat of human immunodeficiency virus 1. Proc Natl Acad Sci U S A,1989.86(13):p.5168-72.
[23]Osborn, L., S. Kunkel and G.J. Nabel, Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A,1989.86(7):p.2336-40.
[24]Shea, L.M., C. Beehler, M. Schwartz, et al., Hyperoxia activates NF-kappaB and increases TNF-alpha and IFN-gamma gene expression in mouse pulmonary lymphocytes. J Immunol,1996.157(9):p.3902-8.
[25]Rupec, R.A. and P.A. Baeuerle, The genomic response of tumor cells to hypoxia and reoxygenation. Differential activation of transcription factors AP-1 and NF-kappa B. Eur J Biochem,1995.234(2):p.632-40.
[26]Mori, N. and D. Prager, Transactivation of the interleukin-lalpha promoter by human T-cell leukemia virus type Ⅰ and type Ⅱ Tax proteins. Blood,1996.87(8):p.3410-7.
[27]Serf ling, E., R. Barthelmas, I. Pfeuffer, et al., Ubiquitous and lymphocyte-specific factors are involved in the induction of the mouse interleukin 2 gene in T lymphocytes. EMBO J,1989.8(2):p.465-73.
[28]Libermann, T.A. and D. Baltimore, Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol,1990.10(5):p.2327-34.
[29]Murphy, T.L., M.G. Cleveland, P. Kulesza, et al., Regulation of interleukin 12 p40 expression through an NF-kappa B half-site. Mol Cell Biol,1995.15(10):p.5258-67.
[30]Shakhov, A.N., M.A. Collart, P. Vassalli, et al., Kappa B-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor alpha gene in primary macrophages. J Exp Med,1990.171(1):p.35-47.
[21]Kunsch, C. and C.A. Rosen, NF-kappa B sub unit-specific regulation of the interleukin-8 promoter. Mol Cell Biol,1993.13(10):p.6137-46.
[32]Grove, M. and M. Plumb, C/EBP, NF-kappa B, and c-Ets family members and transcriptional regulation of the cell-specific and inducible macrophage inflammatory protein 1 alpha immediate-early gene. Mol Cell Biol,1993.13(9):p. 5276-89.
[33]lademarco, M.F., J.J. McQuillan, G.D. Rosen, et al., Characterization of the promoter for vascular cell adhesion molecule-1 (VCAM-1). J Biol Chem,1992.267(23):p. 16323-9.
[34]Lenardo, M.J. and D. Baltimore, NF-kappa B:a pleiotropic mediator of inducible and tissue-specific gene control. Cell,1989.58(2):p.227-9.
[35]Malter, J.S. and M.A. Gerber, Regulation of hepatocyte gene expression:progress on the horizon. Hepatology,1989.10(6):p.1017-8.
[36]Baeuerle, P.A., The inducible transcription activator NF-kappa B:regulation by distinct protein subunits. Biochim Biophys Acta,1991.1072(1):p.63-80.
[37]Siebenlist, U., G. Franzoso and K. Brown, Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol,1994.10:p.405-55.
[38]Finco, T.S. and A.S. Baldwin, Mechanistic aspects of NF-kappa B regulation:the emerging role of phosphorylation and proteolysis. Immunity,1995.3(3):p.263-72.
[39]Schmitz, M.L. and P.A. Baeuerle, Multi-step activation of NF-kappa B/Rel transcription factors. Immunobiology,1995.193(2-4):p.116-27.
[40]Thanos, D. and T. Maniatis, NF-kappa B:a lesson in family values. Cell,1995.80(4):p. 529-32.
[41]Kitamura, M., Control of NF-kappaB and inflammation by the unfolded protein response. Int Rev Immunol,2011.30(1):p.4-15.
[42]Defee, M.R., Z. Qin, L. Dai, et al., Extracellular Hsp90 serves as a co-factor for NF-kappaB activation and cellular pathogenesis induced by an oncogenic herpesvirus. Am J Cancer Res,2011.1(5):p.687-700.
[43]Staudt, L.M., Oncogenic activation of NF-kappaB. Cold Spring Harb Perspect Biol, 2010.2(6):p. a000109.
[44]Iha, H., K.V. Kibler, V.R. Yedavalli, et al., Segregation of NF-kappaB activation through NEMO/IKKgamma by Tax and TNFalpha:implications for stimulus-specific interruption of oncogenic signaling. Oncogene,2003.22(55):p.8912-23.
[45]Mayo, M.W., C.Y. Wang, P.C. Cogswell, et al., Requirement of NF-kappaB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science,1997. 278(5344):p.1812-5.
[46]Galang, C.K., J. Garcia-Ramirez, P.A. Solski, et al., Oncogenic Neu/ErbB-2 increases ets, AP-1, and NF-kappaB-dependent gene expression, and inhibiting ets activation blocks Neu-mediated cellular transformation. J Biol Chem,1996.271(14):p.7992-8.
[47]Wajant, H. and P. Scheurich, TNFR1-induced activation of the classical NF-kappaB pathway. FEBS J,2011.278(6):p.862-76.
[48]Arkan, M.C. and F.R. Greten, IKK-and NF-kappaB-mediated functions in carcinogenesis. Curr Top Microbiol Immunol,2011.349:p.159-69.
[49]Israel, A., The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb Perspect Biol,2010.2(3):p. a000158.
[50]Courtois, G. and A. Israel, IKK regulation and human genetics. Curr Top Microbiol Immunol,2011.349:p.73-95.
[51]Wuerzberger-Davis, S.M. and S. Miyamoto, TAK-ling IKK activation:"Ub" the judge. Sci Signal,2010.3(105):p. pe3.
[52]Shinohara, H., T. Yasuda, Y. Aiba, et al., PKC beta regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1. J Exp Med, 2005.202(10):p.1423-31.
[53]Romashkova, J.A. and S.S. Makarov, NF-kappaB is a target of AKT in anti-apoptotic PDGFsignalling. Nature,1999.401(6748):p.86-90.
[54]Kane, L.P., V.S. Shapiro, D. Stokoe, et al., Induction of NF-kappaB by the Akt/PKB kinase. Curr Biol,1999.9(11):p.601-4.
[55]Arun, P., M.S. Brown, R. Ehsanian, et al., Nuclear NF-kappaB p65 phosphorylation at serine 276 by protein kinase A contributes to the malignant phenotype of head and neck cancer. Clin Cancer Res,2009.15(19):p.5974-84.
[56]Sizemore, N., S. Leung and G.R. Stark, Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-kappaB p65/RelA subunit. Mol Cell Biol,1999.19(7):p.4798-805.
[57]Madrid, L.V., C.Y. Wang, D.C. Guttridge, et al., Akt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-kappaB. Mol Cell Biol,2000.20(5):p.1626-38.
[58]Vermeulen, L., G. De Wilde, P. Van Damme, et al., Transcriptional activation of the NF-kappaB p65 subunit by mitogen-and stress-activated protein kinase-1 (MSK1). EMBO J,2003.22(6):p.1313-24.
[59]Le Page, C., I.H. Koumakpayi, L. Lessard, et al., Independent role of phosphoinositol-3-kinase (PI3K) and casein kinase Ⅱ (CK-2) in EGFR and Her-2-mediated constitutive NF-kappaB activation in prostate cancer cells. Prostate,2005.65(4):p.306-15.
[60]Ten, R.M., C.V. Paya, N. Israel, et al., The characterization of the promoter of the gene encoding the p50 subunit of NF-kappa B indicates that it participates in its own regulation. EMBO J,1992.11(1):p.195-203.
[61]Kanarek, N., N. London, O. Schueler-Furman, et al., Ubiquitination and degradation of the inhibitors of NF-kappaB. Cold Spring Harb Perspect Biol,2010.2(2):p. a000166.
[62]Traenckner, E.B., H.L. Pahl, T. Henkel, et al., Phosphorylation of human I kappa B-alpha on serines 32 and 36 controls I kappa B-alpha proteolysis and NF-kappa B activation in response to diverse stimuli. EMBO J,1995.14(12):p.2876-83.
[63]Tashiro, K., M.P. Pando, Y. Kanegae, et al., Direct involvement of the ubiquitin-conjugating enzyme Ubc9/Hus5 in the degradation of IkappaBalpha. Proc Natl Acad Sci U S A,1997.94(15):p.7862-7.
[64]Kaltschmidt, B., P.A. Baeuerle and C. Kaltschmidt, Potential involvement of the transcription factor NF-kappa B in neurological disorders. Mol Aspects Med,1993. 14(3):p.171-90.
[65]Peltz, G., Transcription factors in immune-mediated disease. Curr Opin Biotechnol, 1997.8(4):p.467-73.
[66]Guijarro, C. and J. Egido, Transcription factor-kappa B (NF-kappa B) and renal disease. Kidney Int,2001.59(2):p.415-24.
[67]Tak, P.P. and G.S. Firestein, NF-kappaB:a key role in inflammatory diseases. J Clin Invest,2001.107(1):p.7-11.
[68]Baldwin, A.S., Jr., Series introduction:the transcription factor NF-kappaB and human disease. J Clin Invest,2001.107(1):p.3-6.
[69]Regnier, C.H., H.Y. Song, X. Gao, et al., Identification and characterization of an IkappaB kinase. Cell,1997.90(2):p.373-83.
[70]DiDonato, J.A., M. Hayakawa, D.M. Rothwarf, et al., A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature,1997.388(6642):p. 548-54.
[71]Mercurio, F., H. Zhu, B.W. Murray, et al., IKK-1 and IKK-2:cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science,1997.278(5339):p.860-6.
[72]Woronicz, J.D., X. Gao, Z. Cao, et al., IkappaB kinase-beta:NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science,1997.278(5339):p. 866-9.
[73]Zhao, J., E. Hoye, S. Boylan, et al., Quaternary structures of a catalytic subunit-regulatory subunit dimeric complex and the holoenzyme of the cAMF-dependent protein kinase by neutron contrast variation. J Biol Chem,1998.273(46):p.30448-59.
[74]Rothwarf, D.M., E. Zandi, G. Natoli, et al., IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature,1998.395(6699):p.297-300.
[75]Maniatis, T., A ubiquitin ligase complex essential for the NF-kappaB, Wnt/Wingless, and Hedgehog signaling pathways. Genes Dev,1999.13(5):p.505-10.
[76]Karin, M. and Y. Ben-Neriah, Phosphorylation meets ubiquitination:the control of NF-[kappa]B activity. Annu Rev Immunol,2000.18:p.621-63.
[77]Chen, Z.J., Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol,2005.7(8):p. 758-65.
[78]Ravid, T. and M. Hochstrasser, NF-kappaB signaling:flipping the switch with polyubiquitin chains. Curr Biol,20,04.14(23):p. R898-900.
[79]Chiu, Y.H., M. Zhao and Z.J. Chen, Ubiquitin in NF-kappaB signaling. Chem Rev,2009. 109(4):p.1549-60.
[80]Israel, A., NF-kappaB activation:Nondegradative ubiquitination implicates NEMO. Trends Immunol,2006.27(9):p.395-7.
[81]Wu, C.J., D.B. Conze, T. Li, et al., Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected]. Nat Cell Biol,2006.8(4):p.398-406.
[82]Sun, L, L. Deng, C.K. Ea, et al., The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell,2004.14(3):p.289-301.
[83]Abbott, D.W., Y. Yang, J.E. Hutti, et al., Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains. Mol Cell Biol,2007.27(17):p. 6012-25.
[84]Boland, M.P., DNA damage signalling and NF-kappaB:implications for survival and death in mammalian cells. Biochem Soc Trans,2001.29(Pt 6):p.674-8.
[85]Zhou, H., I. Wertz, K. O'Rourke, et al., Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature,2004.427(6970):p.167-71.
[86]Oeckinghaus, A., E. Wegener, V. Welteke, et al., Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation. EMBO J,2007.26(22):p.4634-45.
[87]Kovalenko, A., C. Chable-Bessia, G. Cantarella, et al., The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature,2003. 424(6950):p.801-5.
[88]Brummelkamp, T.R., S.M. Nijman, A.M. Dirac, et al., Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature,2003. 424(6950):p.797-801.
[89]Wertz, I.E., K.M. O'Rourke, H. Zhou, et al., De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature,2004.430(7000):p. 694-9.
[90]Mauro, C., F. Pacifico, A. Lavorgna, et al., ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB. J Biol Chem,2006.281(27):p.18482-8.
[91]Grilli, M. and M. Memo, Possible role of NF-kappaB and p53 in the glutamate-induced pro-apoptotic neuronal pathway. Cell Death Differ,1999.6(1):p.22-7.
[92]Rocha, S. and N.D. Perkins, ARF the integrator:linking NF-kappaB, p53 and checkpoint kinases. Cell Cycle,2005.4(6):p.756-9.
[93]Karin, M., The NF-kappa B activation pathway:its regulation and role in inflammation and cell survival. Cancer J Sci Am,1998.4 Suppl 1:p. S92-9.
[94]Jones, P.L., D. Ping and J.M. Boss, Tumor necrosis factor alpha and interleukin-1beta regulate the murine manganese superoxide dismutase gene through a complex intronic enhancer involving C/EBP-beta and NF-kappaB. Mol Cell Biol,1997.17(12):p. 6970-81.
[95]Joyce, D., C. Albanese, J. Steer, et al., NF-kappaB and cell-cycle regulation:the cyclin connection. Cytokine Growth Factor Rev,2001.12(1):p.73-90.
[96]Pidgeon, G.P., J.H. Harmey, E. Kay, et al., The role of endotoxin/lipopolysaccharide in surgically induced tumour growth in a murine model of metastatic disease. Br J Cancer,1999.81(8):p.1311-7.
[97]Greten, F.R., L. Eckmann, T.F. Greten, et al., IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell,2004.118(3):p. 285-96.
[98]Luo, J.L., H. Kamata and M. Karin, IKK/NF-kappaB signaling:balancing life and death--a new approach to cancer therapy. J Clin Invest,2005.115(10):p.2625-32.
[99]Potter, J.D. and C.M. Ulrich, COX-2 and gastric cancer:More on inflammation and neoplasia. Gastroenterology,2006.130(7):p.2198-200.
[100]Hahm, K.B., H.Y. Lim, S. Sohn, et al., In vitro evidence of the role of COX-2 in attenuating gastric inflammation and promoting gastric carcinogenesis. J Environ Pathol Toxicol Oncol,2002.21(2):p.165-76.
[101]Pikarsky, E., R.M. Porat, I. Stein, et al., NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature,2004.431(7007):p.461-6.
[102]Feng, X.H. and R. Derynck, Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol,2005.21:p.659-93.
[103]Derynck, R. and Y.E. Zhang, Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature,2003.425(6958):p.577-84.
[104]Massague, J., TGFbeta in Cancer. Cell,2008.134(2):p.215-30.
[105]Petrocca, F., R. Visone, M.R. Onelli, et al., E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell, 2008.13(3):p.272-86.
[106]Massague, J., How cells read TGF-beta signals. Nat Rev Mol Cell Biol,2000.1(3):p. 169-78.
[107]Itoh, S., F. Itoh, M.J. Goumans, et al., Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem,2000.267(24):p.6954-67.
[108]Moustakas, A., S. Souchelnytskyi and C.H. Heldin, Smad regulation in TGF-beta signal transduction. J Cell Sci,2001.114(Pt 24):p.4359-69.
[109]Gentry, L.E., M.N. Lioubin, A.F. Purchio, et al., Molecular events in the processing of recombinant type 1 pre-pro-transforming growth factor beta to the mature polypeptide. Mol Cell Biol,1988.8(10):p.4162-8.
[110]Derynck, R., J.A. Jarrett, E.Y. Chen, et al., Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature,1985.316(6030):p.701-5.
[111]Gentry, L.E., N.R. Webb, G.J. Lim, et al., Type 1 transforming growth factor beta: amplified expression and secretion of mature and precursor polypeptides in Chinese hamster ovary cells. Mol Cell Biol,1987.7(10):p.3418-27.
[112]Miyazono, K., H. Ichijo and C.H. Heldin, Transforming growth factor-beta:latent forms, binding proteins and receptors. Growth Factors,1993.8(1):p.11-22.
[113]Taipale, J., K. Miyazono, C.H. Heldin, et al., Latent transforming growth factor-beta 1 associates to fibroblast extracellular matrix via latent TGF-beta binding protein. J Cell Biol,1994.124(1-2):p.171-81.
[114]Nunes, I., P.E. Gleizes, C.N. Metz, et al., Latent transforming growth factor-beta binding protein domains involved in activation and transglutaminase-dependent cross-linking of latent transforming growth factor-beta. J Cell Biol,1997.136(5):p. 1151-63.
[115]Ueno, N., N. Ling, S.Y. Ying, et al., Isolation and partial characterization of follistatin: a single-chain Mr 35,000 monomeric protein that inhibits the release of follicle-stimulating hormone. Proc Natl Acad Sci U S A,1987.84(23):p.8282-6.
[116]de Winter, J.P., P. ten Dijke, C.J. de Vries, et al., Follistatins neutralize activin bioactivity by inhibition of activin binding to its type Ⅱ receptors. Mol Cell Endocrinol, 1996.116(1):p.105-14.
[117]Zimmerman, L.B., J.M. De Jesus-Escobar and R.M. Harland, The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4. Cell,1996.86(4): p.599-606.
[118]Piccolo, S., Y. Sasai, B. Lu, et al., Dorsoventral patterning in Xenopus:inhibition of ventral signals by direct binding of chordin to BMP-4. Cell,1996.86(4):p.589-98.
[119]Kretzschmar, M., J. Doody, I. Timokhina, et al., A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev,1999.13(7):p.804-16.
[120]Engel, M.E., M.A. McDonnell, B.K. Law, et al., Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription. J Biol Chem, 1999.274(52):p.37413-20.
[121]Wicks, S.J., S. Lui, N. Abdel-Wahab, et al., Inactivation of smad-transforming growth factor beta signaling by Ca(2+)-calmodulin-dependent protein kinase II. Mol Cell Biol, 2000.20(21):p.8103-11.
[122]Arora, K. and R. Warrior, A new Smurf in the village. Dev Cell,2001.1(4):p.441-2.
[123]Zhu, H., P. Kavsak, S. Abdollah, et al., A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation. Nature,1999.400(6745):p.687-93.
[124]Zhang, Y., C. Chang, D.J. Gehling, et al., Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc Natl Acad Sci U S A,2001.98(3):p.974;9.
[125]Inman, G.J., F.J. Nicolas and C.S. Hill, Nucleocytoplasmic shuttling of Smads 2,3, and 4 permits sensing of TGF-beta receptor activity. Mol Cell,2002.10(2):p.283-94.
[126]Watanabe, M., N. Masuyama, M. Fukuda, et al., Regulation of intracellular dynamics of Smad4 by its leucine-rich nuclear export signal. EMBO Rep,2000.1(2):p.176-82.
[127]Xiao, Z., N. Watson, C. Rodriguez, et al., Nucleocytoplasmic shuttling of Smadl conferred by its nuclear localization and nuclear export signals. J Biol Chem,2001. 276(42):p.39404-10.
[128]Xu, L., Y.G. Chen and J. Massague, The nuclear import function of Smad2 is masked by SARA and unmasked by TGFbeta-dependent phosphorylation. Nat Cell Biol,2000. 2(8):p.559-62.
[129]Kurisaki, A., S. Kose, Y. Yoneda, et al., Transforming growth factor-beta induces nuclear import of Smad3 in an importin-betal and Ran-dependent manner. Mol Biol Cell,2001.12(4):p.1079-91.
[130]Xu, L., Y. Kang, S. Col, et al., Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFbeta signaling complexes in the cytoplasm and nucleus. Mol Cell,2002.10(2):p.271-82.
[131]Akhurst, R.J. and R. Derynck, TGF-beta signaling in cancer--a double-edged sword. Trends Cell Biol,2001.11(11):p. S44-51.
[132]Shi, Y., Y.F. Wang, L. Jayaraman, et al., Crystal structure of a Smad MH1 domain bound to DNA:insights on DNA binding in TGF-beta signaling. Cell,1998.94(5):p. 585-94.
[133]Derynck, R., Y. Zhang and X.H. Feng, Smads:transcriptional activators of TGF-beta responses. Cell,1998.95(6):p.737-40.
[134]Germain, S., M. Howell, G.M. Esslemont, et al., Homeodomain and winged-helix transcription factors recruit activated Smads to distinct promoter elements via a common Smad interaction motif. Genes Dev,2000.14(4):p.435-51.
[135]Luo, K., S.L. Stroschein, W. Wang, et al., The Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signaling. Genes Dev,1999.13(17):p.2196-206.
[136]Sun, Y., X. Liu, E. Ng-Eaton, et al., SnoN and Ski protooncoproteins are rapidly degraded in response to transforming growth factor beta signaling. Proc Natl Acad Sci U S A,1999.96(22):p.12442-7.
[137]Wotton, D., R.S. Lo, S. Lee, et al., A Smad transcriptional corepressor. Cell,1999. 97(1):p.29-39.
[138]Feng, X.H., Y. Zhang, R.Y. Wu, et al., The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for smad3 in TGF-beta-induced transcriptional activation. Genes Dev,1998.12(14):p.2153-63.
[139]Wang, G., J. Long, I. Matsuura, et al., The Smad3 linker region contains a transcriptional activation domain. Biochem J,2005.386(Pt 1):p.29-34.
[140]Kim, R.H., D. Wang, M. Tsang, et al., A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction. Genes Dev,2000.14(13): p.1605-16.
[141]Endo, F., S. Kubo, H. Awata, et al., Complete rescue of lethal albino d4CoS mice by null mutation of 4-hydroxyphenylpyruvate dioxygenase and induction of apoptosis of hepatocytes in these mice by in vivo retrieval of the tyrosine catabolic pathway. J Biol Chem,1997.272(39):p.24426-32.
[142]Endo, F., H. Katoh, S. Yamamoto, et al., A murine model for type Ⅲ tyrosinemia:lack of immunologically detectable 4-hydroxyphenylpyruvic acid dioxygenase enzyme protein in a novel mouse strain with hypertyrosinemia. Am J Hum Genet,1991.48(4): p.704-9.
[143]Hager, S.E., R.I. Gregerman and W.E. Knox, p-Hydroxyphenylpyruvate oxidase of liver. J Biol Chem,1957.225(2):p.935-47.
[144]Nakai, C., M. Nozaki and O. Hayaishi, Studies on a possible reaction intermediate of p-hydroxyphenylpyruvate dioxygenase. Biochem Biophys Res Commun,1975.67(2): p.590-5.
[145]Borowski, T., A. Bassan and P.E. Siegbahn,4-Hydroxyphenylpyruvate dioxygenase:a hybrid density functional study of the catalytic reaction mechanism. Biochemistry, 2004.43(38):p.12331-42.
[146]Neve, S., L. Aarenstrup, D. Tornehave, et al., Tissue distribution, intracellular localization and proteolytic processing of rat 4-hydroxyphenylpyruvate dioxygenase. Cell Biol Int,2003.27(8):p.611-24.
[147]Lee, M.H., Z.H. Zhang, C.H. MacKinnon, et al., The C-terminal of rat 4-hydroxyphenylpyruvate dioxygenase is indispensable for enzyme activity. FEBS Lett, 1996.393(2-3):p.269-72.
[148]Wong, K.K., T. Jacks and G. Dranoff, NF-kappaB fans the flames of lung carcinogenesis. Cancer Prev Res (Phila),2010.3(4):p.403-5.
[149]Hanahan, D. and R.A. Weinberg, Hallmarks of cancer:the next generation. Cell,2011. 144(5):p.646-74.
[150]Chen, F., Y. Lu, Z. Zhang, et al., Opposite effect of NF-kappa B and c-Jun N-terminal kinase on p53-independent GADD45 induction by arsenite. J Biol Chem,2001. 276(14):p.11414-9.
[151]Karin, M. and A. Lin, NF-kappaB at the crossroads of life and death. Nat Immunol, 2002.3(3):p.221-7.
[152]Ju, W., X. Wang, H. Shi, et al., A critical role of luteolin-induced reactive oxygen species in blockage of tumor necrosis factor-activated nuclear factor-kappaB pathway and sensitization of apoptosis in lung cancer cells. Mol Pharmacol,2007. 71(5):p.1381-8.
[153]Kim, K.M. and Y.J. Lee, Amiloride augments TRAIL-induced apoptotic death by inhibiting phosphorylation of kinases and phosphatases associated with the P13K-Akt pathway. Oncogene,2005.24(3):p.355-66.
[154]Lin, Y., L. Bai, W. Chen, et al., The NF-kappaB activation pathways, emerging molecular targets for cancer prevention and therapy. Expert Opin Ther Targets,2010. 14(1):p.45-55.
[155]Wang, X. and Y. Lin, Tumor necrosis factor and cancer, buddies or foes? Acta Pharmacol Sin,2008.29(11):p.1275-88.
[156]Grivennikov, S.I., F.R. Greten and M. Karin, Immunity, inflammation, and cancer. Cell, 2010.140(6):p.883-99.
[157]Abbott, D.W., A. Wilkins, J.M. Asara, et al., The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr Biol, 2004.14(24):p.2217-27.
[158]Warburg, O., On respiratory impairment in cancer cells. Science,1956.124(3215):p. 269-70.
[159]Warburg, O., On the origin of cancer cells. Science,1956.123(3191):p.309-14.
[160]Vander Heiden, M.G., L.C. Cantley and C.B. Thompson, Understanding the Warburg effect:the metabolic requirements of cell proliferation. Science,2009.324(5930):p. 1029-33.
[161]Kawauchi, K., K. Araki, K. Tobiume, et al., p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nat Cell Biol,2008. 10(5):p.611-8.
[162]Morgan, M.J. and Z.G. Liu, Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res,2011.21(1):p.103-15.
[163]Villanueva, A., C. Garcia, A.B. Paules, et al., Disruption of the antiproliferative TGF-beta signaling pathways in human pancreatic cancer cells. Oncogene,1998.17(15): p.1969-78.
[164]Tang, B., E.P. Bottinger, S.B. Jakowlew, et al., Transforming growth factor-betal is a new form of tumor suppressor with true haploid insufficiency. Nat Med,1998.4(7):p. 802-7.
[165]Mukhopadhyay, T., J.A. Roth and S.A. Maxwell, Altered expression of the p50 subunit of the NF-kappa B transcription factor complex in non-small cell lung carcinoma. Oncogene,1995.11(5):p.999-1003.
[166]Pietenpol, J.A., R.W. Stein, E. Moran, et al., TGF-beta 1 inhibition of c-myc transcription and growth in keratinocytes is abrogated by viral transforming proteins with pRB binding domains. Cell,1990.61(5):p.777-85.
[167]Polyak, K., J.Y. Kato, M.J. Solomon, et al., p27Kipl, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest. Genes Dev,1994.8(1):p.9-22.
[168]. Alexandrow, M.G. and H.L. Moses, Transforming growth factor beta and cell cycle regulation. Cancer Res,1995.55(7):p.1452-7.
[169]Wang, X., W. Ju, J. Renouard, et al.,17-allylamino-17-demethoxygeldanamycin synergistically potentiates tumor necrosis factor-induced lung cancer cell death by blocking the nuclear factor-kappaB pathway. Cancer Res,2006.66(2):p.1089-95.
[170]Datto, M.B., Y. Li, J.F. Panus, et al., Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci U S A,1995.92(12):p.5545-9.
[171]Markowitz, S.D. and A.B. Roberts, Tumor suppressor activity of the TGF-beta pathway in human cancers. Cytokine Growth Factor Rev,1996.7(1):p.93-102.
[172]Barbie, D.A., P. Tamayo, J.S. Boehm, et al., Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature,2009.462(7269):p.108-12.
[173]Ishitani, T., J. Ninomiya-Tsuji, S. Nagai, et al., The TAKl-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. Nature, 1999.399(6738):p.798-802.
[174]Takada, I., M. Mihara, M. Suzawa, et al., A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat Cell Biol,2007.9(11):p.1273-85.
[175]Kortenjann, M., M. Nehls, A.J. Smith, et al., Abnormal bone marrow stroma in mice deficient for nemo-like kinase, Nlk. Eur J Immunol,2001.31(12):p.3580-7.
[176]Kojima, H., T. Sasaki, T. Ishitani, et al., STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFbeta-activated kinase 1 for STAT3 Ser-727 phosphorylation. Proc Natl Acad Sci U S A,2005.102(12):p.4524-9.
[177]Labbe, E., A. Letamendia and L. Attisano, Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-beta and wnt pathways. Proc Natl Acad Sci U S A,2000. 97(15):p.8358-63.
[178]Yasuda, J., H. Yokoo, T. Yamada, et al., Nemo-like kinase suppresses a wide range of transcription factors, including nuclear factor-kappaB. Cancer Sci,2004.95(1):p.52-7.
[179]Ehrlich, M., D. Horbelt, B. Marom, et al., Homomeric and heteromeric complexes among TGF-beta and BMP receptors and their roles in signaling. Cell Signal,2011. 23(9):p.1424-32.
[180]Lan, H.Y. and A.C. Chung, Transforming growth factor-beta and Smads. Contrib Nephrol,2011.170:p.75-82.
[181]Ishitani, T., J. Ninomiya-Tsuji and K. Matsumoto, Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related Nemo-like kinase-dependent phosphorylation in Wnt/beta-catenin signaling. Mol Cell Biol,2003.23(4): p.1379-89.
[1]Sen, R. and D. Baltimore, Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell,1986.46(5):p.705-16.
[2]Sen, R. and D. Baltimore, Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell,1986.47(6):p.921-8.
[3]Baeuerle, P.A. and D. Baltimore, A 65-kappaD subunit of active NF-kappaB is required for inhibition of NF-kappaB by I kappaB. Genes Dev,1989.3(11):p.1689-98.
[4]Ghosh, S., A.M. Gifford, L.R. Riviere, et al., Cloning of the p50 DNA binding subunit of NF-kappa B:homology to rel and dorsal. Cell,1990.62(5):p.1019-29.
[5]Kieran, M., V. Blank, F. Logeat, et al., The DNA binding subunit of NF-kappa B is identical to factor KBF1 and homologous to the rel oncogene product. Cell,1990. 62(5):p.1007-18.
[6]Nolan, G.P., S. Ghosh, H.C. Liou, et al., DNA binding and I kappa B inhibition of the cloned p65 subunit of NF-kappa B, a rel-related polypeptide. Cell,1991.64(5):p.961-9.
[7]Ruben, S.M., P.J. Dillon, R. Schreck, et al., Isolation of a rel-related human cDNA that potentially encodes the 65-kD subunit of NF-kappa B. Science,1991.254(5028):p.11.
[8]Neri, A., C.C. Chang, L. Lombardi, et al., B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-kappa B p50. Cell,1991.67(6):p.1075-87.
[9]Hayden, M.S. and S. Ghosh, NF-kappaB, the first quarter-century:remarkable progress and outstanding questions. Genes Dev,2012.26(3):p.203-34.
[10]Haskill, S., A.A. Beg, S.M. Tompkins, et al., Characterization of an immediate-early gene induced in adherent monocytes that encodes I kappa B-like activity. Cell,1991. 65(7):p.1281-9.
[11]Davis, N., S. Ghosh, D.L. Simmons, et al., Rel-associated pp40:an inhibitor of the rel family of transcription factors. Science,1991.253(5025):p.1268-71.
[12]Kerr, L.D., J. Inoue, N. Davis, et al., The rel-associated pp40 protein prevents DNA binding of Rel and NF-kappa B:relationship with I kappa B beta and regulation by phosphorylation. Genes Dev,1991.5(8):p.1464-76.
[13]Thompson, J.E., R.J. Phillips, H. Erdjument-Bromage, et al.,I kappa B-beta regulates the persistent response in a biphasic activation of NF-kappa B. Cell,1995.80(4):p. 573-82.
[14]Wulczyn, F.G., M. Naumann and C. Scheidereit, Candidate proto-oncogene bcl-3 encodes a subunit-specific inhibitor of transcription factor NF-kappa B. Nature,1992. 358(6387):p.597-9.
[15]Yamazaki, S., T. Muta and K. Takeshige, A novel IkappaB protein, IkappaB-zeta, induced by proinflammatory stimuli, negatively regulates nuclear factor-kappaB in the nuclei. J Biol Chem,2001.276(29):p.27657-62.
[16]Henkel, T., T. Machleidt, I. Alkalay, et al., Rapid proteolysis of I kappa B-alpha is necessary for activation of transcription factor NF-kappa B. Nature,1993.365(6442): p.182-5.
[17]Alkalay, I., A. Yaron, A. Hatzubai, et al., Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A,1995.92(23):p.10599-603.
[18]Chen, Z., J. Hagler, V.J. Palombella, et al., Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. Genes Dev,1995. 9(13):p.1586-97.
[19]Regnier, C.H., H.Y. Song, X. Gao, et al., Identification and characterization of an IkappaB kinase. Cell,1997.90(2):p.373-83.
[20]DiDonato, J.A., M. Hayakawa, D.M. Rothwarf, et al., A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature,1997.388(6642):p. 548-54.
[21]Zandi, E., D.M. Rothwarf, M. Delhase, et al., The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell,1997.91(2):p.243-52.
[22]Mercurio, F., H. Zhu, B.W. Murray, et al., IKK-1 and IKK-2:cytokine-activated IkappaB kinases essential for NF-kappaB activation. Science,1997.278(5339):p.860-6.
[23]Woronicz, J.D., X. Gao, Z. Cao, et al., IkappaB kinase-beta:NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science,1997.278(5339):p. 866-9.
[24]Yamaoka, S., G. Courtois, C. Bessia, et al., Complementation cloning of NEMO, a component of the IkappaB kinase complex essential for NF-kappaB activation. Cell, 1998.93(7):p.1231-40.
[25]Rothwarf, D.M., E. Zandi, G. Natoli, et al., IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex. Nature,1998.395(6699):p.297-300.
[26]Tang, E.D., C,Y. Wanr, Y. Xiong, et al., A role for NF-kappaB essential modifier/lkappaB kinase-gamma (NEMO/IKKgamma) ubiquitination in the activation of the IkappaB kinase complex by tumor necrosis factor-alpha. J Biol Chem,2003. 278(39):p.37297-305.
[27]Stilo, R., D. Liguoro, B. Di Jeso, et al., Physical and functional interaction of CARMA1 and CARMA3 with Ikappa kinase gamma-NFkappaB essential modulator. J Biol Chem, 2004.279(33):p.34323-31.
[28]Zhang, S.Q., A. Kovalenko, G. Cantarella, et al., Recruitment of the IKK signalosome to the p55 TNF receptor:RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation. Immunity,2000.12(3):p.301-11.
[29]Wu, C.J. and J.D. Ashwell, NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-kappaB activation. Proc Natl Acad Sci U S A,2008.105(8): p.3023-8.
[30]Cooke, E.L., I.J. Uings, C.L. Xia, et al.. Functional analysis of the interleukin-1-receptor-associated kinase (IRAK-1) in interleukin-1 beta-stimulated nuclear factor kappa B (NF-kappa B) pathway activation:IRAK-1 associates with the NF-kappa B essential modulator (NEMO) upon receptor stimulation. Biochem J,2001.359(Pt 2): p.403-10.
[31]Windheim, M., M. Stafford, M. Peggie, et al., Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase. Mol Cell Biol,2008.28(5):p. 1783-91.
[32]Chariot, A., A. Leonardi, J. Muller, et al., Association of the adaptor TANK with the I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases. J Biol Chem,2002.277(40):p.37029-36.
[33]Bonif, M., M.A. Meuwis, P. Close, et al., TNFalpha- and IKKbeta-mediated TANK/I-TRAF phosphorylation:implications for interaction with NEMO/IKKgamma and NF-kappaB activation. Biochem J,2006.394(Pt 3):p.593-603.
[34]Miranda, C., E. Roccato, G. Raho, et al., The TFG protein, involved in oncogenic rearrangements, interacts with TANK and NEMO, two proteins involved in the NF-kappaB pathway. J Cell Physiol,2006.208(1):p.154-60.
[35]Poyet, J.L., S.M. Srinivasula and E.S. Alnemri, vCLAP, a caspase-recruitment domain-containing protein of equine Herpesvirus-2, persistently activates the Ikappa B kinases through oligomerization of IKKgamma. J Biol Chem,2001.276(5):p.3183-7.
[36]Liu, L., M.T. Eby, N. Rathore, et al., The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Ikappa B kinase complex. J Biol Chem,2002.277(16):p.13745-51.
[37]Field, N., W. Low, M. Daniels, et al., KSHV vFLIP binds to IKK-gamma to activate IKK. J Cell Sci,2003.116(Pt 18):p.3721-8.
[38]Shifera, A.S., Proteins that bind to IKKgamma (NEMO) and down-regulate the activation of NF-kappaB. Biochem Biophys Res Commun,2010.396(3):p.585-9.
[39]Lee, E.G., D.L. Boone, S. Chai, et al., Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science,2000.289(5488):p.2350-4.
[40]He, K.L. and A.T. Ting, A20 inhibits tumor necrosis factor (TNF) alpha-induced apoptosis by disrupting recruitment of TRADD and RIP to the TNF receptor 1 complex in Jurkat T cells. Mol Cell Biol,2002.22(17):p.6034-45.
[41]Wertz, I.E., K.M. O'Rourke, H. Zhou, et al., De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature,2004.430(7000):p. 694-9.
[42]Stilo, R., E. Varricchio, D. Liguoro, et al., A20 is a negative regulator of BCL10-and CARMA3-mediated activation of NF-kappaB. J Cell Sci,2008.121(Pt 8):p.1165-71.
[43]Oshima, S., E.E. Turer, J.A. Callahan, et al., ABIN-1 is a ubiquitin sensor that restricts cell death and sustains embryonic development. Nature,2009.457(7231):p.906-9.
[44]Wagner, S., I. Carpentier, V. Rogov, et al., Ubiquitin binding mediates the NF-kappaB inhibitory potential of ABIN proteins. Oncogene,2008.27(26):p.3739-45.
[45]Kovalenko, A., C. Chable-Bessia, G. Cantarella, et al., The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature,2003. 424(6950):p.801-5.
[46]Brummelkamp, T.R., S.M. Nijman, A.M. Dirac, et al., Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature,2003. 424(6950):p.797-801.
[47]Reiley, W., M. Zhang, X. Wu, et al., Regulation of the deubiquitinating enzyme CYLD by IkappaB kinase gamma-dependent phosphorylation. Mol Cell Biol,2005.25(10):p. 3886-95.
[48]Ashida, H., M. Kim, M. Schmidt-Supprian, et al., A bacterial E3 ubiquitin ligase lpaH9.8 targets NEMO/IKKgamma to dampen the host NF-kappaB-mediated inflammatory response. Nat Cell Biol,2010.12(1):p.66-73; sup pp 1-9.
[49]Huang, T.T., S.M. Wuerzberger-Davis, Z.H. Wu, et al., Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. Cell,2003.115(5):p.565-76.
[50]Habraken, Y. and J. Piette, NF-kappaB activation by double-strand breaks. Biochem Pharmacol,2006.72(9):p.1132-41.
[51]Janssens, S. and J. Tschopp, Signals from within:the DNA-damage-induced NF-kappaB response. Cell Death Differ,2006.13(5):p.773-84.
[52]Sebban, H., S. Yamaoka and G. Courtois, Posttranslational modifications of NEMO and its partners in NF-kappaB signaling. Trends Cell Biol,2006.16(11):p.569-77.
[53]Janssens, S., A. Tinel, S. Lippens, et al., PIDD mediates NF-kappaB activation in re(?)ponse to DNA damage. Cell,2005.123(6):p.1079-92.
[54]Wu, Z.H., Y. Shi, R.S. Tibbetts, et al., Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli. Science,2006.311(5764):p. 1141-6.
[55]Wuerzberger-Davis, S.M., Y. Nakamura, B.J. Seufzer, et al., NF-kappaB activation by combinations of NEMO SUMOylation and ATM activation stresses in the absence of DNA damage. Oncogene,2007.26(5):p.641-51.
[56]Mabb, A.M., S.M. Wuerzberger-Davis and S. Miyamoto, PIASy mediates NEMO sumoylation and NF-kappaB activation in response to genotoxic stress. Nat Cell Biol, 2006.8(9):p.986-93.