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Regulation of Programmed Cell Death by NF-κB and its Role in Tumorigenesis and Therapy

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Programmed Cell Death in Cancer Progression and Therapy

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 615))

The Rel/NF-κB transcription factors are key regulators of programmed cell death (PCD). Their activity has significant physiological relevance for normal development and homeostasis in various tissues and important pathological consequences are associated with aberrant NF-κB activity, including hepatocyte apoptosis, neurodegeneration, and cancer. While NF-κB is best characterized for its protective activity in response to proapoptotic stimuli, its role in suppressing programmed necrosis has come to light more recently. NF-κB most commonly antagonizes PCD by activating the expression of antiapoptotic proteins and antioxidant molecules, but it can also promote PCD under certain conditions and in certain cell types. It is therefore important to understand the pathways that control NF-κB activation in different settings and the mechanisms that regulate its anti- vs pro-death activities. Here, we review the role of NF-κB in apoptotic and necrotic PCD, the mechanisms involved, and how its activity in the cell death response impacts cancer development, progression, and therapy. Given the role that NF-κB plays both in tumor cells and in the tumor microenvironment, recent findings underscore the NF-κB signaling pathway as a promising target for cancer prevention and treatment.

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References

  • Alcamo, E., Mizgerd, J. P., Horwitz, B. H., Bronson, R., Beg, A. A., Scott, M., Doerschuk, C. M., Hynes, R. O., and Baltimore, D. (2001). Targeted mutation of TNF receptor I rescues the RelA-deficient mouse and reveals a critical role for NF-kappa B in leukocyte recruitment. J Immunol 167, 1592–1600.

    CAS  Google Scholar 

  • Alizadeh, A., Eisen, M., Davis, R., Ma, C., Lossos, I., Rosenwald, A., Boldrick, J., Sabet, H., Tran, T., Yu, X., Powell, J., Yang, L., Marti, G., Moore, T., Hudson, J. J., Lu, L., Lewis, D., Tibshirani, R., Sherlock, G., Chan, W., Greiner, T., Weisenburger, D. D., Armitage, J. O., Warnke, R., Levy, R., Wilson, W. H., Greyer, M. R., Byrd, J., Botstein, D., Brown, P. O., and Staudt, L. M. (2000). Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511.

    CAS  Google Scholar 

  • Amanullah, A., Azam, N., Balliet, A., Hollander, C., Hoffman, B., Fornace, A., and Liebermann, D. (2003). Cell signalling: cell survival and a Gadd45-factor deficiency. Nature 424, 741; discussion 742.

    Google Scholar 

  • Arsura, M., Panta, G. R., Bilyeu, J. D., Cavin, L. G., Sovak, M. A., Oliver, A. A., Factor, V., Heuchel, R., Mercurio, F., Thorgeirsson, S. S., and Sonenshein, G. E. (2003). Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation. Oncogene 22, 412–425.

    CAS  Google Scholar 

  • Ashikawa, K., Shishodia, S., Fokt, I., Priebe, W., and Aggarwal, B. B. (2004). Evidence that activation of nuclear factor-kappaB is essential for the cytotoxic effects of doxorubicin and its analogues. Biochem Pharmacol 67, 353–364.

    CAS  Google Scholar 

  • Baetz, D., Regula, K. M., Ens, K., Shaw, J., Kothari, S., Yurkova, N., and Kirshenbaum, L. A. (2005). Nuclear factor-kappaB-mediated cell survival involves transcriptional silencing of the mitochondrial death gene BNIP3 in ventricular myocytes. Circulation 112, 3777–3785.

    CAS  Google Scholar 

  • Baldwin, A. S. (2001). Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest 107, 241–246.

    CAS  Google Scholar 

  • Bargou, R., Emmerich, F., Krappmann, D., Bommert, K., Mapara, M., Arnold, W., Royer, H., Grinstein, E., Greiner, A., Scheidereit, C., and Dorken, B. (1997). Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin’s disease tumor cells. J Clin Invest 100, 2961–2969.

    CAS  Google Scholar 

  • Barkett, M. and Gilmore, T. D. (1999). Control of apoptosis by Rel/NF-kappaB transcription factors. Oncogene 18, 6910–6924.

    CAS  Google Scholar 

  • Barth, T. F., Dohner, H., Werner, C. A., Stilgenbauer, S., Schlotter, M., Pawlita, M., Lichter, P., Moller, P., and Bentz, M. (1998). Characteristic pattern of chromosomal gains and losses in primary large B-cell lymphomas of the gastrointestinal tract. Blood 91, 4321–4330.

    CAS  Google Scholar 

  • Barth, T. F., Martin-Subero, J. I., Joos, S., Menz, C. K., Hasel, C., Mechtersheimer, G., Parwaresch, R. M., Lichter, P., Siebert, R., and Moeller, P. (2003). Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin lymphoma. Blood 101, 3681–3686.

    CAS  Google Scholar 

  • Beg, A. A. and Baltimore, D. (1996). An essential role for NF- B in preventing TNF-B-induced cell death. Science 274, 782–784.

    CAS  Google Scholar 

  • Bernard, D., Quatannens, B., Vandenbunder, B., and Abbadie, C. (2001a). Rel/NF-kappaB transcription factors protect against tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by up-regulating the TRAIL decoy receptor DcR1. J Biol Chem 276, 27322–27328.

    CAS  Google Scholar 

  • Bernard, D., Slomianny, C., Vandenbunder, B., and Abbadie, C. (2001b). cRel induces mitochondrial alterations in correlation with proliferation arrest. Free Radic Biol Med 31, 943–953.

    CAS  Google Scholar 

  • Bernard, D., Monte, D., Vandenbunder, B., and Abbadie, C. (2002). The c-Rel transcription factor can both induce and inhibit apoptosis in the same cells via the upregulation of MnSOD. Oncogene 21, 4392–4402.

    CAS  Google Scholar 

  • Bharti, A. C., Donato, N., Singh, S., and Aggarwal, B. B. (2003). Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Blood 101, 1053–1062.

    CAS  Google Scholar 

  • Biswas, D. K., Shi, Q., Baily, S., Strickland, I., Ghosh, S., Pardee, A. B., and Iglehart, J. D. (2004). NF-kappa B activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proc Natl Acad Sci USA 101, 10137–10142.

    CAS  Google Scholar 

  • Bonizzi, G. and Karin, M. (2004). The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25, 280–288.

    CAS  Google Scholar 

  • Brambilla, R., Bracchi-Ricard, V., Hu, W. H., Frydel, B., Bramwell, A., Karmally, S., Green, E. J., and Bethea, J. R. (2005). Inhibition of astroglial nuclear factor kappaB reduces inflammation and improves functional recovery after spinal cord injury. J Exp Med 202, 145–156.

    CAS  Google Scholar 

  • Brummelkamp, T. R., Nijman, S. M., Dirac, A. M., and Bernards, R. (2003). Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature 424, 797–801.

    CAS  Google Scholar 

  • Budd, R. C., Yeh, W. C., and Tschopp, J. (2006). cFLIP regulation of lymphocyte activation and development. Nat Rev Immunol 6, 196–204.

    CAS  Google Scholar 

  • Campbell, K. J., Rocha, S., and Perkins, N. D. (2004). Active repression of antiapoptotic gene expression by RelA(p65) NF-kappa B. Mol Cell 13, 853–865.

    CAS  Google Scholar 

  • Campbell, K. J., Witty, J. M., Rocha, S., and Perkins, N. D. (2006). Cisplatin mimics ARF tumor suppressor regulation of RelA (p65) nuclear factor-kappaB transactivation. Cancer Res 66, 929–935.

    CAS  Google Scholar 

  • Cavin, L. G., Romieu-Mourez, R., Panta, G. R., Sun, J., Factor, V. M., Thorgeirsson, S. S., Sonenshein, G. E., and Arsura, M. (2003). Inhibition of CK2 activity by TGF-beta1 promotes IkappaB-alpha protein stabilization and apoptosis of immortalized hepatocytes. Hepatology 38, 1540–1551.

    CAS  Google Scholar 

  • Cavin, L. G., Venkatraman, M., Factor, V. M., Kaur, S., Schroeder, I., Mercurio, F., Beg, A. A., Thorgeirsson, S. S., and Arsura, M. (2004). Regulation of alpha-fetoprotein by nuclear factor-kappaB protects hepatocytes from tumor necrosis factor-alpha cytotoxicity during fetal liver development and hepatic oncogenesis. Cancer Res 64, 7030–7038.

    CAS  Google Scholar 

  • Chen, X., Kandasamy, K., and Srivastava, R. K. (2003). Differential roles of RelA (p65) and c-Rel subunits of nuclear factor kappa B in tumor necrosis factor-related apoptosis-inducing ligand signaling. Cancer Res 63, 1059–1066.

    CAS  Google Scholar 

  • Claudio, E., Brown, K., and Siebenlist, U. (2006). NF-kappaB guides the survival and differentiation of developing lymphocytes. Cell Death Differ 13, 697–701.

    CAS  Google Scholar 

  • Crumrine, R. C., Thomas, A. L., and Morgan, P. F. (1994). Attenuation of p53 expression protects against focal ischemic damage in transgenic mice. J Cereb Blood Flow Metab 14, 887–891.

    CAS  Google Scholar 

  • Currier, N., Solomon, S. E., Demicco, E. G., Chang, D. L., Farago, M., Ying, H., Dominguez, I., Sonenshein, G. E., Cardiff, R. D., Xiao, Z. X., Sherr, D. H., and Seldin, D. C. (2005). Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors. Toxicol Pathol 33, 726–737.

    CAS  Google Scholar 

  • Daido, S., Kanzawa, T., Yamamoto, A., Takeuchi, H., Kondo, Y., and Kondo, S. (2004). Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res 64, 4286–4293.

    CAS  Google Scholar 

  • Dajee, M., Lazarov, M., Zhang, J. Y., Cai, T., Green, C. L., Russell, A. J., Marinkovich, M. P., Tao, S., Lin, Q., Kubo, Y., and Khavari, P. A. (2003). NF-kB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421, 639–643.

    CAS  Google Scholar 

  • Davis, R. E., Brown, K. D., Siebenlist, U., and Staudt, L. M. (2001). Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 194, 1861–1874.

    CAS  Google Scholar 

  • Davis, R. J. (2000). Signal transduction by the JNK group of MAP kinases. Cell 103, 239–252.

    CAS  Google Scholar 

  • De Smaele, E., Zazzeroni, F., Papa, S., Nguyen, D. U., Jin, R., Jones, J., Cong, R., and Franzoso, G. (2001). Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. Nature 414, 308–313.

    Google Scholar 

  • de Visser, K. E. and Coussens, L. M. (2005). The interplay between innate and adaptive immunity regulates cancer development. Cancer Immunol Immunother 54, 1143–1152.

    Google Scholar 

  • Delhalle, S., Deregowski, V., Benoit, V., Merville, M. P., and Bours, V. (2002). NF-kappaB-dependent MnSOD expression protects adenocarcinoma cells from TNF-alpha-induced apoptosis. Oncogene 21, 3917–3924.

    CAS  Google Scholar 

  • Deveraux, Q. L., Takahashi, R., Salvesen, G. S. and Reed, J. C. (1997). X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388, 300–304.

    CAS  Google Scholar 

  • Do, R. K., Hatada, E., Lee, H., Tourigny, M. R., Hilbert, D., and Chen-Kiang, S. (2000). Attenuation of apoptosis underlies B lymphocyte stimulator enhancement of humoral immune response. J Exp Med 192, 953–964.

    CAS  Google Scholar 

  • Doi, T. S., Marino, M. W., Takahashi, T., Yoshida, T., Sakakura, T., Old, L. J., and Obata, Y. (1999). Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality. Proc Natl Acad Sci USA 96, 2994–2999.

    CAS  Google Scholar 

  • Duckett, C. S. (2005). IAP proteins: sticking it to Smac. Biochem J 385, e1–e2.

    CAS  Google Scholar 

  • Edinger, A. L. and Thompson, C. B. (2004). Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol 16, 663–669.

    CAS  Google Scholar 

  • Egan, L. J., Eckmann, L., Greten, F. R., Chae, S., Li, Z. W., Myhre, G. M., Robine, S., Karin, M., and Kagnoff, M. F. 2004. IkappaB-kinasebeta-dependent NF-kappaB activation provides radioprotection to the intestinal epithelium. Proc Natl Acad Sci USA 101, 2452–2457.

    CAS  Google Scholar 

  • Fan, Y., Dutta, J., Gupta, N., and Gélinas, C. (2006). Molecular basis of oncogenesis by NF-kB: from a bird’s eye view to a RELevant role in cancer. In: NF-kB/Rel Transcription Factor Family, ed. Liou, H. C. Landes Bioscience Publishers, Georgetown, TX, pp. 112–130.

    Google Scholar 

  • Feng, B., Cheng, S., Hsia, C. Y., King, L. B., Monroe, J. G., and Liou, H. C. (2004). NF-kappaB inducible genes BCL-X and cyclin E promote immature B-cell proliferation and survival. Cell Immunol 232, 9–20.

    CAS  Google Scholar 

  • Fernandez, Y., Verhaegen, M., Miller, T. P., Rush, J. L., Steiner, P., Opipari, A. W., Jr., Lowe, S. W., and Soengas, M. S. (2005). Differential regulation of noxa in normal melanocytes and melanoma cells by proteasome inhibition: therapeutic implications. Cancer Res 65, 6294–6304.

    CAS  Google Scholar 

  • Feuerhake, F., Kutok, J. L., Monti, S., Chen, W., LaCasce, A. S., Cattoretti, G., Kurtin, P., Pinkus, G. S., de Leval, L., Harris, N. L., Savage, K. J., Neuberg, D., Habermann, T. M., Dalla-Favera, R., Golub, T. R., Aster, J. C., and Shipp, M. A. (2005). NFkappaB activity, function, and target-gene signatures in primary mediastinal large B-cell lymphoma and diffuse large B-cell lymphoma subtypes. Blood 106, 1392–1399.

    CAS  Google Scholar 

  • Garkavtsev, I., Kozin, S. V., Chernova, O., Xu, L., Winkler, F., Brown, E., Barnett, G. H., and Jain, R. K. (2004). The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis. Nature 428, 328–332.

    CAS  Google Scholar 

  • Gerondakis, S. and Strasser, A. (2003). The role of Rel/NF-kappaB transcription factors in B lymphocyte survival. Semin Immunol 15, 159–166.

    CAS  Google Scholar 

  • Gilmore, T., Gapuzan, M. E., Kalaitzidis, D., and Starczynowski, D. (2002). Rel/NF-kB/IkB signal transduction in the generation and treatment of human cancer. Cancer Lett 181, 1–9.

    CAS  Google Scholar 

  • Gilmore, T. D. (1999). Multiple mutations contribute to the oncogenicity of the retroviral oncoprotein v-Rel. Oncogene 18, 6925–6937.

    CAS  Google Scholar 

  • Gilmore, T. D., Kalaitzidis, D., Liang, M. C., and Starczynowski, D. T. (2004). The c-Rel transcription factor and B-cell proliferation: a deal with the devil. Oncogene 23, 2275–2286.

    CAS  Google Scholar 

  • Goudeau, B., Huetz, F., Samson, S., Di Santo, J. P., Cumano, A., Beg, A., Israel, A., and Memet, S. (2003). IkappaBalpha/IkappaBepsilon deficiency reveals that a critical NF-kappaB dosage is required for lymphocyte survival. Proc Natl Acad Sci USA 100, 15800–15805.

    CAS  Google Scholar 

  • Greten, F. R., Eckmann, L., Greten, T. F., Park, J. M., Li, Z. W., Egan, L. J., Kagnoff, M. F., and Karin, M. (2004). IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296.

    CAS  Google Scholar 

  • Grossmann, M., O’Reilly, L. A., Gugasyan, R., Strasser, A., Adams, J. M., and Gerondakis, S. (2000). The anti-apoptotic activities of Rel and RelA required during B-cell maturation involve the regulation of Bcl-2 expression. EMBO J 19, 6351–6360.

    CAS  Google Scholar 

  • Grumont, R. J., Rourke, I. J., O’Reilly, L. A., Strasser, A., Miyake, K., Sha, W., and Gerondakis, S. (1998). B lymphocytes differentially use the Rel and nuclear factor kB1 (NF-kB1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. J Exp Med 187, 663–674.

    CAS  Google Scholar 

  • Grumont, R. J., Rourke, I. J., and Gerondakis, S. (1999). Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes Dev 13, 400–411.

    CAS  Google Scholar 

  • Gugasyan, R., Christou, A., O’Reilly L, A., Strasser, A., and Gerondakis, S. (2006). Bcl-2 transgene expression fails to prevent fatal hepatocyte apoptosis induced by endogenous TNFalpha in mice lacking RelA. Cell Death Differ 13(7), 1235–1237.

    CAS  Google Scholar 

  • Hait, W. N., Jin, S., and Yang, J. M. (2006). A matter of life or death (or both): understanding autophagy in cancer. Clin Cancer Res 12, 1961–1965.

    CAS  Google Scholar 

  • Hayden, M. S. and Ghosh, S. (2004). Signaling to NF-kappaB. Genes Dev 18, 2195–2224.

    CAS  Google Scholar 

  • Headon, D. J., Emmal, S. A., Ferguson, B. M., Tucker, A. S., Justice, M. J., Sharpe, P. T., Zonana, J., and Overbeek, P. A. (2001). Gene defect in ectodermal dysplasia implicates a death domain adapter in development. Nature 414, 913–916.

    CAS  Google Scholar 

  • Hettmann, T., DiDonato, J., Karin, M., and Leiden, J. M. (1999). An essential role for nuclear factor kappaB in promoting double positive thymocyte apoptosis. J Exp Med 189, 145–158.

    CAS  Google Scholar 

  • Heusch, M., Lin, L., Geleziunas, R., and Greene, W. C. (1999). The generation of nfkb2 p52: mechanism and efficiency. Oncogene 18, 6201–6208.

    CAS  Google Scholar 

  • Hinz, M., Loser, P., Mathas, S., Krappmann, D., Dorken, B., and Scheidereit, C. (2001). Constitutive NF-kappaB maintains high expression of a characteristic gene network, including CD40, CD86, and a set of antiapoptotic genes in Hodgkin/Reed-Sternberg cells. Blood 97, 2798–2807.

    CAS  Google Scholar 

  • Hiscott, J., Kwon, H., and Genin, P. (2001). Hostile takeovers: viral appropriation of the NF-kappaB pathway. J Clin Invest 107, 143–151.

    CAS  Google Scholar 

  • Hofmann, C. S. and Sonenshein, G. E. (2003). Green tea polyphenol epigallocatechin-3 gallate induces apoptosis of proliferating vascular smooth muscle cells via activation of p53. FASEB J 17, 702–704.

    CAS  Google Scholar 

  • Houldsworth, J., Mathew, S., Rao, P. H., Dyomina, K., Louie, D. C., Parsa, N., Offit, K., and Chaganti, R. S. K. (1996). REL proto-oncogene is frequently amplified in extranodal diffuse large cell lymphoma. Blood 87, 25–29.

    CAS  Google Scholar 

  • Hsu, B. L., Harless, S. M., Lindsley, R. C., Hilbert, D. M., and Cancro, M. P. (2002). Cutting edge: BLyS enables survival of transitional and mature B cells through distinct mediators. J Immunol 168, 5993–5996.

    CAS  Google Scholar 

  • Jaattela, M. and Tschopp, J. (2003). Caspase-independent cell death in T lymphocytes. Nat Immunol 4, 416–423.

    Google Scholar 

  • Javelaud, D. and Besancon, F. (2001). NF-kappa B activation results in rapid inactivation of JNK in TNF alpha-treated Ewing sarcoma cells: a mechanism for the anti-apoptotic effect of NF-kappa B. Oncogene 20, 4365–4372.

    CAS  Google Scholar 

  • John, G. R., Lee, S. C., and Brosnan, C. F. (2003). Cytokines: powerful regulators of glial cell activation. Neuroscientist 9, 10–22.

    CAS  Google Scholar 

  • Joos, S., Otano-Joos, M. I., Ziegler, S., Brüderlein, S., du Manoir, S., Bentz, M., Möller, P., and Lichter, P. (1996). Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. Blood 87, 1571–1578.

    CAS  Google Scholar 

  • Joos, S., Menz, C. K., Wrobel, G., Siebert, R., Gesk, S., Ohl, S., Mechtersheimer, G., Trumper, L., Moller, P., Lichter, P., and Barth, T. F. (2002). Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2. Blood 99, 1381–1387.

    CAS  Google Scholar 

  • Kamata, H. and Hirata, H. (1999). Redox regulation of cellular signalling. Cell Signal 11, 1–14.

    CAS  Google Scholar 

  • Kamata, H., Honda, S., Maeda, S., Chang, L., Hirata, H., and Karin, M. (2005). Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120, 649–661.

    CAS  Google Scholar 

  • Kanzawa, T., Zhang, L., Xiao, L., Germano, I. M., Kondo, Y., and Kondo, S. (2005). Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. Oncogene 24, 980–991.

    CAS  Google Scholar 

  • Karin, M., Cao, Y., Greten, F. R., and Li, Z. W. (2002). NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2, 301–310.

    CAS  Google Scholar 

  • Karin, M., Yamamoto, Y., and Wang, Q. M. (2004). The IKK NF-kappa B system: a treasure trove for drug development. Nat Rev Drug Discov 3, 17–26.

    CAS  Google Scholar 

  • Kasibhatla, S., Genestier, L., and Green, D. R. (1999). Regulation of fas-ligand expression during activation-induced cell death in T lymphocytes via nuclear factor kB. J Biol Chem 274, 987–992.

    CAS  Google Scholar 

  • Kaur, S., Wang, F., Venkatraman, M., and Arsura, M. (2005). X-linked inhibitor of apoptosis (XIAP) inhibits c-Jun N-terminal kinase 1 (JNK1) activation by transforming growth factor beta1 (TGF-beta1) through ubiquitin-mediated proteosomal degradation of the TGF-beta1-activated kinase 1 (TAK1). J Biol Chem 280, 38599–38608.

    CAS  Google Scholar 

  • Khoshnan, A., Bae, D., Tindell, C. A., and Nel, A. E. (2000). The physical association of protein kinase C theta with a lipid raft-associated inhibitor of kappa B factor kinase (IKK) complex plays a role in the activation of the NF-kappa B cascade by TCR and CD28. J Immunol 165, 6933–6940.

    CAS  Google Scholar 

  • Kim, H. J., Hawke, N., and Baldwin, A. S. (2006). NF-kappaB and IKK as therapeutic targets in cancer. Cell Death Differ 13, 738–747.

    CAS  Google Scholar 

  • Kontgen, F., Grumont, R. J., Strasser, A., Metcalf, D., Li, R., Tarlinton, D., and Gerondakis, S. (1995). Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev 9, 1965–1977.

    CAS  Google Scholar 

  • Kopp, E. and Ghosh, S. (1994). Inhibition of NF-KB by sodium salycilate and aspirin. Science 265, 956.

    CAS  Google Scholar 

  • Kordes, U., Krappmann, D., Heissmeyer, V., Ludwig, W. D., and Scheidereit, C. (2000). Transcription factor NF-kB is constitutively activated in acute lymphoblastic leukemia cells. Leukemia 14, 399–402.

    CAS  Google Scholar 

  • Kovalenko, A., Chable-Bessia, C., Cantarella, G., Israel, A., Wallach, D., and Courtois, G. (2003). The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 424, 801–805.

    CAS  Google Scholar 

  • Kreuz, S., Siegmund, D., Rumpf, J. J., Samel, D., Leverkus, M., Janssen, O., Hacker, G., Dittrich-Breiholz, O., Kracht, M., Scheurich, P., and Wajant, H. (2004). NFkappaB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP. J Cell Biol 166, 369–380.

    CAS  Google Scholar 

  • Kucharczak, J. F., Simmons, M. J., Fan, Y., and Gelinas, C. (2003). To be, or not to be: NF-kappaB is the answer–role of Rel/NF-kappaB in the regulation of apoptosis. Oncogene 22, 8961–8982.

    CAS  Google Scholar 

  • Lam, L. T., Davis, R. E., Pierce, J., Hepperle, M., Xu, Y., Hottelet, M., Nong, Y., Wen, D., Adams, J., Dang, L., and Staudt, L. M. (2005). Small molecule inhibitors of IkappaB kinase are selectively toxic for subgroups of diffuse large B-cell lymphoma defined by gene expression profiling. Clin Cancer Res 11, 28–40.

    CAS  Google Scholar 

  • Landowski, T. H., Megli, C. J., Nullmeyer, K. D., Lynch, R. M., and Dorr, R. T. (2005). Mitochondrial-mediated disregulation of Ca2+ is a critical determinant of Velcade (PS-341/bortezomib) cytotoxicity in myeloma cell lines. Cancer Res 65, 3828–3836.

    CAS  Google Scholar 

  • Leist, M. and Jaattela, M. (2001). Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2, 589–598.

    CAS  Google Scholar 

  • Leitges, M., Sanz, L., Martin, P., Duran, A., Braun, U., Garcia, J. F., Camacho, F., Diaz-Meco, M. T., Rennert, P. D., and Moscat, J. (2001). Targeted disruption of the zetaPKC gene results in the impairment of the NF-kappaB pathway. Mol Cell 8, 771–780.

    CAS  Google Scholar 

  • Levine, B. and Yuan, J. (2005). Autophagy in cell death: an innocent convict? J Clin Invest 115, 2679–2688.

    CAS  Google Scholar 

  • Li, Q. and Verma, I. M. (2002). NF-kappaB regulation in the immune system. Nat Rev Immunol 2, 725–734.

    CAS  Google Scholar 

  • Li, Q., Van Antwerp, D., Mercurio, F., Lee, K. F., and Verma, I. M. (1999a). Severe liver degeneration in mice lacking the IkappaB kinase 2 gene. Science 284, 321–325.

    CAS  Google Scholar 

  • Li, Q., Estepa, G., Memet, S., Israel, A., and Verma, I. M. (2000). Complete lack of NF-kappaB activity in IKK1 and IKK2 double-deficient mice: additional defect in neurulation. Genes Dev 14, 1729–1733.

    CAS  Google Scholar 

  • Li, Q., Withoff, S., and Verma, I. M. (2005). Inflammation-associated cancer: NF-kappaB is the lynchpin. Trends Immunol 26, 318–325.

    Google Scholar 

  • Li, Z. W., Chu, W., Hu, Y., Delhase, M., Deerinck, T., Ellisman, M., Johnson, R., and Karin, M. (1999b). The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J Exp Med 189, 1839–1845.

    CAS  Google Scholar 

  • Li, Z. W., Omori, S. A., Labuda, T., Karin, M., and Rickert, R. C. (2003). IKK beta is required for peripheral B cell survival and proliferation. J Immunol 170, 4630–4637.

    CAS  Google Scholar 

  • Liang, C., Zhang, M., and Sun, S. C. (2006). beta-TrCP binding and processing of NF-kappaB2/p100 involve its phosphorylation at serines 866 and 870. Cell Signal 18(8), 1309–1317.

    CAS  Google Scholar 

  • Lin, B., Williams-Skipp, C., Tao, Y., Schleicher, M. S., Cano, L. L., Duke, R. C., and Scheinman, R. I. (1999). NF-kappaB functions as both a proapoptotic and antiapoptotic regulatory factor within a single cell type. Cell Death Differ 6, 570–582.

    CAS  Google Scholar 

  • Liston, P., Fong, W. G., and Korneluk, R. G. (2003). The inhibitors of apoptosis: there is more to life than Bcl2. Oncogene 22, 8568–8580.

    CAS  Google Scholar 

  • Liu, N., Raja, S. M., Zazzeroni, F., Metkar, S. S., Shah, R., Zhang, M., Wang, Y., Bromme, D., Russin, W. A., Lee, J. C., Peter, M. E., Froelich, C. J., Franzoso, G., and Ashton-Rickardt, P. G. (2003). NFkappaB protects from the lysosomal pathway of cell death. EMBO J 22, 5313–5322.

    CAS  Google Scholar 

  • Lotze, M. T. and Tracey, K. J. (2005). High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 5, 331–342.

    CAS  Google Scholar 

  • Lu, D., Thompson, J. D., Gorski, G. K., Rice, N. R., Mayer, M. G., and Yunis, J. J. (1991). Alterations at the rel locus in human lymphoma. Oncogene 6, 1235–1241.

    CAS  Google Scholar 

  • Luo, J. L., Maeda, S., Hsu, L. C., Yagita, H., and Karin, M. (2004). Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell 6, 297–305.

    CAS  Google Scholar 

  • Luo, J. L., Kamata, H., and Karin, M. (2005a). The anti-death machinery in IKK/NF-kappaB signaling. J Clin Immunol 25, 541–550.

    CAS  Google Scholar 

  • Luo, J. L., Kamata, H., and Karin, M. (2005b). IKK/NF-kappaB signaling: balancing life and death–a new approach to cancer therapy. J Clin Invest 115, 2625–2632.

    CAS  Google Scholar 

  • Maeda, S., Kamata, H., Luo, J. L., Leffert, H., and Karin, M. (2005). IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977–990.

    CAS  Google Scholar 

  • Martin, P., Duran, A., Minguet, S., Gaspar, M. L., Diaz-Meco, M. T., Rennert, P., Leitges, M., and Moscat, J. (2002). Role of zeta PKC in B-cell signaling and function. EMBO J 21, 4049–4057.

    CAS  Google Scholar 

  • Mathas, S., Lietz, A., Janz, M., Hinz, M., Jundt, F., Scheidereit, C., Bommert, K., and Dorken, B. (2003). Inhibition of NF-kappaB essentially contributes to arsenic-induced apoptosis. Blood 102, 1028–1034.

    CAS  Google Scholar 

  • Matsuzawa, A. and Ichijo, H. (2005). Stress-responsive protein kinases in redox-regulated apoptosis signaling. Antioxid Redox Signal 7, 472–481.

    CAS  Google Scholar 

  • Mattson, M. P. and Camandola, S. (2001). NF-kappaB in neuronal plasticity and neurodegenerative disorders. J Clin Invest 107, 247–254.

    CAS  Google Scholar 

  • Mattson, M. P. and Meffert, M. K. (2006). Roles for NF-kappaB in nerve cell survival, plasticity, and disease. Cell Death Differ 13, 852–860.

    CAS  Google Scholar 

  • Micheau, O. and Tschopp, J. (2003). Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190.

    CAS  Google Scholar 

  • Micheau, O., Lens, S., Gaide, O., Alevizopoulos, K., and Tschopp, J. (2001). NF-kappaB signals induce the expression of c-FLIP. Mol Cell Biol 21, 5299–5305.

    CAS  Google Scholar 

  • Morrison, R. S., Wenzel, H. J., Kinoshita, Y., Robbins, C. A., Donehower, L. A., and Schwartzkroin, P. A. (1996). Loss of the p53 tumor suppressor gene protects neurons from kainate-induced cell death. J Neurosci 16, 1337–1345.

    CAS  Google Scholar 

  • Nakanishi, C. and Toi, M. (2005). Nuclear factor-kappaB inhibitors as sensitizers to anticancer drugs. Nat Rev Cancer 5, 297–309.

    CAS  Google Scholar 

  • Nakano, H., Nakajima, A., Sakon-Komazawa, S., Piao, J. H., Xue, X., and Okumura, K. (2006). Reactive oxygen species mediate crosstalk between NF-kappaB and JNK. Cell Death Differ 13, 730–737.

    CAS  Google Scholar 

  • Ngo, V. N., Davis, R. E., Lamy, L., Yu, X., Zhao, H., Lenz, G., Lam, L. T., Dave, S., Yang, L., Powell, J., and Staudt, L. M. (2006). A loss-of-function RNA interference screen for molecular targets in cancer. Nature 441, 106–110.

    CAS  Google Scholar 

  • Owyang, A. M., Tumang, J. R., Schram, B. R., Hsia, C. Y., Behrens, T. W., Rothstein, T. L., and Liou, H. C. (2001). c-Rel is required for the protection of B cells from antigen receptor-mediated, but not Fas-mediated, apoptosis. J Immunol 167, 4948–4956.

    CAS  Google Scholar 

  • Papa, S., Zazzeroni, F., Bubici, C., Jayawardena, S., Alvarez, K., Matsuda, S., Nguyen, D. U., Pham, C. G., Nelsbach, A. H., Melis, T., De Smaele, E., Tang, W. J., D’Adamio, L., and Franzoso, G. (2004a). Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2. Nat Cell Biol 6, 146–153.

    CAS  Google Scholar 

  • Papa, S., Zazzeroni, F., Pham, C. G., Bubici, C., and Franzoso, G. (2004b). Linking JNK signaling to NF-kappaB: a key to survival. J Cell Sci 117, 5197–5208.

    CAS  Google Scholar 

  • Papa, S., Bubici, C., Zazzeroni, F., Pham, C. G., Kuntzen, C., Knabb, J. R., Dean, K., and Franzoso, G. (2006). The NF-kappaB-mediated control of the JNK cascade in the antagonism of programmed cell death in health and disease. Cell Death Differ 13, 712–729.

    CAS  Google Scholar 

  • Park, J. S., Gamboni-Robertson, F., He, Q., Svetkauskaite, D., Kim, J. Y., Strassheim, D., Sohn, J. W., Yamada, S., Maruyama, I., Banerjee, A., Ishizaka, A., and Abraham, E. (2006). High mobility group box 1 protein interacts with multiple Toll-like receptors. Am J Physiol Cell Physiol 290, C917–924.

    CAS  Google Scholar 

  • Pasparakis, M., Courtois, G., Hafner, M., Schmidt-Supprian, M., Nenci, A., Toksoy, A., Krampert, M., Goebeler, M., Gillitzer, R., Israel, A., Krieg, T., Rajewsky, K., and Haase, I. (2002a). TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417, 861–866.

    CAS  Google Scholar 

  • Pasparakis, M., Schmidt-Supprian, M., and Rajewsky, K. (2002b). IkappaB kinase signaling is essential for maintenance of mature B cells. J Exp Med 196, 743–752.

    CAS  Google Scholar 

  • Perkins, N. D. (2004). NF-kappaB: tumor promoter or suppressor? Trends Cell Biol 14, 64–69.

    CAS  Google Scholar 

  • Perkins, N. D. and Gilmore, T. D. (2006). Good cop, bad cop: the different faces of NF-kappaB. Cell Death Differ 13, 759–772.

    CAS  Google Scholar 

  • Petro, J. B. and Khan, W. N. (2001). Phospholipase C-gamma 2 couples Bruton’s tyrosine kinase to the NF-kappaB signaling pathway in B lymphocytes. J Biol Chem 276, 1715–1719.

    CAS  Google Scholar 

  • Petro, J. B., Rahman, S. M., Ballard, D. W., and Khan, W. N. (2000). Bruton’s tyrosine kinase is required for activation of IkappaB kinase and nuclear factor kappaB in response to B cell receptor engagement. J Exp Med 191, 1745–1754.

    CAS  Google Scholar 

  • Pham, C. G., Bubici, C., Zazzeroni, F., Papa, S., Jones, J., Alvarez, K., Jayawardena, S., De Smaele, E., Cong, R., Beaumont, C., Torti, F. M., Torti, S. V., and Franzoso, G. (2004). Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Cell 119, 529–542.

    CAS  Google Scholar 

  • Pikarsky, E., Porat, R. M., Stein, I., Abramovitch, R., Amit, S., Kasem, S., Gutkovich-Pyest, E., Urieli-Shoval, S., Galun, E., and Ben-Neriah, Y. (2004). NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466.

    CAS  Google Scholar 

  • Prendes, M., Zheng, Y., and Beg, A. A. (2003). Regulation of developing B cell survival by RelA-containing NF-kappa B complexes. J Immunol 171, 3963–3969.

    CAS  Google Scholar 

  • Qing, G. and Xiao, G. (2005). Essential role of IkappaB kinase alpha in the constitutive processing of NF-kappaB2 p100. J Biol Chem 280, 9765–9768.

    CAS  Google Scholar 

  • Qing, G., Qu, Z., and Xiao, G. (2005). Stabilization of basally translated NF-kappaB-inducing kinase (NIK) protein functions as a molecular switch of processing of NF-kappaB2 p100. J Biol Chem 280, 40578–40582.

    CAS  Google Scholar 

  • Rao, P. H., Houldsworth, J., Dyomina, K., Parsa, N. Z., Cigudosa, J. C., Louie, D. C., Popplewell, L., Offit, K., Jhanwar, S. C., and Chaganti, R. S. (1998). Chromosomal and gene amplification in diffuse large B-cell lymphoma. Blood 92, 234–240.

    CAS  Google Scholar 

  • Rape, M. and Jentsch, S. (2004). Productive RUPture: activation of transcription factors by proteasomal processing. Biochim Biophys Acta 1695, 209–213.

    CAS  Google Scholar 

  • Rayet, B. and Gelinas, C. (1999). Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18, 6938–6947.

    CAS  Google Scholar 

  • Richardson, P. G., Hideshima, T., Mitsiades, C., and Anderson, K. (2004). Proteasome inhibition in hematologic malignancies. Ann Med 36, 304–314.

    CAS  Google Scholar 

  • Robe, P. A., Bentires-Alj, M., Bonif, M., Rogister, B., Deprez, M., Haddada, H., Khac, M. T., Jolois, O., Erkmen, K., Merville, M. P., Black, P. M., and Bours, V. (2004). In vitro and in vivo activity of the nuclear factor-kappaB inhibitor sulfasalazine in human glioblastomas. Clin Cancer Res 10, 5595–5603.

    CAS  Google Scholar 

  • Rocha, S., Campbell, K. J., and Perkins, N. D. (2003). p53- and Mdm2-independent repression of NF-kappa B transactivation by the ARF tumor suppressor. Mol Cell 12, 15–25.

    CAS  Google Scholar 

  • Rocha, S., Garrett, M. D., Campbell, K. J., Schumm, K., and Perkins, N. D. (2005). Regulation of NF-kappaB and p53 through activation of ATR and Chk1 by the ARF tumour suppressor. EMBO J 24, 1157–1169.

    CAS  Google Scholar 

  • Rudolph, D., Yeh, W. C., Wakeham, A., Rudolph, B., Nallainathan, D., Potter, J., Elia, A. J., and Mak, T. W. (2000). Severe liver degeneration and lack of NF-kappaB activation in NEMO/IKKgamma-deficient mice. Genes Dev 14, 854–862.

    CAS  Google Scholar 

  • Ryo, A., Suizu, F., Yoshida, Y., Perrem, K., Liou, Y. C., Wulf, G., Rottapel, R., Yamaoka, S., and Lu, K. P. (2003). Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol Cell 12, 1413–1426.

    CAS  Google Scholar 

  • Sakon, S., Xue, X., Takekawa, M., Sasazuki, T., Okazaki, T., Kojima, Y., Piao, J. H., Yagita, H., Okumura, K., Doi, T., and Nakano, H. (2003). NF-kappaB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death. EMBO J 22, 3898–3909.

    CAS  Google Scholar 

  • Sanna, M. G., da Silva Correia, J., Ducrey, O., Lee, J., Nomoto, K., Schrantz, N., Deveraux, Q. L., and Ulevitch, R. J. (2002). IAP suppression of apoptosis involves distinct mechanisms: the TAK1/JNK1 signaling cascade and caspase inhibition. Mol Cell Biol 22, 1754–1766.

    CAS  Google Scholar 

  • Santoro, M. G., Rossi, A., and Amici, C. (2003). NF-kappaB and virus infection: who controls whom. EMBO J 22, 2552–2560.

    CAS  Google Scholar 

  • Savage, K. J., Monti, S., Kutok, J. L., Cattoretti, G., Neuberg, D., De Leval, L., Kurtin, P., Dal Cin, P., Ladd, C., Feuerhake, F., Aguiar, R. C., Li, S., Salles, G., Berger, F., Jing, W., Pinkus, G. S., Habermann, T., Dalla-Favera, R., Harris, N. L., Aster, J. C., Golub, T. R., and Shipp, M. A. (2003). The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102, 3871–3879.

    CAS  Google Scholar 

  • Scaffidi, P., Misteli, T., and Bianchi, M. E. (2002). Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195.

    CAS  Google Scholar 

  • Schiemann, B., Gommerman, J. L., Vora, K., Cachero, T. G., Shulga-Morskaya, S., Dobles, M., Frew, E., and Scott, M. L. (2001). An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293, 2111–2114.

    CAS  Google Scholar 

  • Schmidt-Supprian, M., Bloch, W., Courtois, G., Addicks, K., Israel, A., Rajewsky, K., and Pasparakis, M. (2000). NEMO/IKK gamma-deficient mice model incontinentia pigmenti. Mol Cell 5, 981–992.

    CAS  Google Scholar 

  • Schmidt-Ullrich, R., Aebischer, T., Hulsken, J., Birchmeier, W., Klemm, U., and Scheidereit, C. (2001). Requirement of NF-kappaB/Rel for the development of hair follicles and other epidermal appendices. Development 128, 3843–3853.

    CAS  Google Scholar 

  • Seitz, C. S., Deng, H., Hinata, K., Lin, Q., and Khavari, P. A. (2000). Nuclear factor kappaB subunits induce epithelial cell growth arrest. Cancer Res 60, 4085–4092.

    CAS  Google Scholar 

  • Seitz, C. S., Lin, Q., Deng, H. and Khavari, P. A. (1998). Alterations in NF-kappaB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-kappaB. Proc Natl Acad Sci USA 95, 2307–2312.

    CAS  Google Scholar 

  • Senftleben, U., Cao, Y., Xiao, G., Greten, F. R., Krahn, G., Bonizzi, G., Chen, Y., Hu, Y., Fong, A., Sun, S. C., and Karin, M. (2001). Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 293, 1495–1499.

    CAS  Google Scholar 

  • Shipp, M., Ross, K., Tamayo, P., Weng, A. P., Kutok, J. L., Aguiar, R. C. T., Gaasenbeek, M., Angelo, M., Reich, M., Pinkus, G. S., Ray, T. S., Koval, M. A., Last, K. W., Norton, A., Lister, A., Mesirov, J., Neuberg, D. S., Lander, E. S., Aster, J. C., and Golub, T. R. (2002). Diffuse large B-cell lymphoma outcome prediction by gene expression profiling and supervised machine learning. Nat Med 8, 68–74.

    CAS  Google Scholar 

  • Siebenlist, U., Brown, K., and Claudio, E. (2005). Control of lymphocyte development by nuclear factor-kappaB. Nat Rev Immunol 5, 435–445.

    CAS  Google Scholar 

  • Signorelli, P. and Ghidoni, R. (2005). Resveratrol as an anticancer nutrient: molecular basis, open questions and promises. J Nutr Biochem 16, 449–466.

    CAS  Google Scholar 

  • Small, G. W., Shi, Y. Y., Edmund, N. A., Somasundaram, S., Moore, D. T., and Orlowski, R. Z. (2004). Evidence that mitogen-activated protein kinase phosphatase-1 induction by proteasome inhibitors plays an antiapoptotic role. Mol Pharmacol 66, 1478–1490.

    CAS  Google Scholar 

  • Sonenshein, G. E. (1997). Rel/NF-kappa B transcription factors and the control of apoptosis. Semin Cancer Biol 8, 113–119.

    CAS  Google Scholar 

  • Stark, L. A. and Dunlop, M. G. (2005). Nucleolar sequestration of RelA (p65) regulates NF-kappaB-driven transcription and apoptosis. Mol Cell Biol 25, 5985–6004.

    CAS  Google Scholar 

  • Subhashini, J., Mahipal, S. V., and Reddanna, P. (2005). Anti-proliferative and apoptotic effects of celecoxib on human chronic myeloid leukemia in vitro. Cancer Lett 224, 31–43.

    CAS  Google Scholar 

  • Tacconelli, A., Farina, A.R., Cappabianca, L., Desantis, G., Tessitore, A., Vetuschi, A., Sferra, R., Rucci, N., Argenti, B., Screpanti, I., Gulino, A., Mackay, A.R. (2004). TrkA alternative splicing: a regulated tumor-promoting switch in human neuroblastoma. Cancer Cell 6, 347–360.

    CAS  Google Scholar 

  • Takada, Y., Bhardwaj, A., Potdar, P., and Aggarwal, B. B. (2004). Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-kappaB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation. Oncogene 23, 9247–9258.

    CAS  Google Scholar 

  • Tan, J. E., Wong, S. C., Gan, S. K., Xu, S., and Lam, K. P. (2001). The adaptor protein BLNK is required for b cell antigen receptor-induced activation of nuclear factor-kappa B and cell cycle entry and survival of B lymphocytes. J Biol Chem 276, 20055–20063.

    CAS  Google Scholar 

  • Tanaka, H., Matsumura, I., Ezoe, S., Satoh, Y., Sakamaki, T., Albanese, C., Machii, T., Pestell, R. G. and Kanakura, Y. (2002). E2F1 and c-Myc potentiate apoptosis through inhibition of NF-kappaB activity that facilitates MnSOD-mediated ROS elimination. Mol Cell 9, 1017–1029.

    CAS  Google Scholar 

  • Tanaka, M., Fuentes, M. E., Yamaguchi, K., Durnin, M. H., Dalrymple, S. A., Hardy, K. L., and Goeddel, D. V. (1999). Embryonic lethality, liver degeneration, and impaired NF-kappa B activation in IKK-beta-deficient mice. Immunity 10, 421–429.

    CAS  Google Scholar 

  • Tang, G., Minemoto, Y., Dibling, B., Purcell, N. H., Li, Z., Karin, M., and Lin, A. (2001). Inhibition of JNK activation through NF-kappaB target genes. Nature 414, 313–317.

    CAS  Google Scholar 

  • Tao, Y., Yan, D., Yang, Q., Zeng, R., and Wang, Y. (2006). Low K+ promotes NF-kappaB/DNA binding in neuronal apoptosis induced by K+ loss. Mol Cell Biol 26, 1038–1050.

    CAS  Google Scholar 

  • Tergaonkar, V., Pando, M., Vafa, O., Wahl, G., and Verma, I. (2002). p53 stabilization is decreased upon NFkappaB activation: a role for NFkappaB in acquisition of resistance to chemotherapy. Cancer Cell 1, 493–503.

    CAS  Google Scholar 

  • Trompouki, E., Hatzivassiliou, E., Tsichritzis, T., Farmer, H., Ashworth, A., and Mosialos, G. (2003). CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 424, 793–796.

    CAS  Google Scholar 

  • Tumang, J. R., Owyang, A., Andjelic, S., Jin, Z., Hardy, R. R., Liou, M. L., and Liou, H. C. (1998). c-Rel is essential for B lymphocyte survival and cell cycle progression. Eur J Immunol 28, 4299–4312.

    CAS  Google Scholar 

  • Vakkila, J. and Lotze, M. T. (2004). Inflammation and necrosis promote tumour growth. Nat Rev Immunol 4, 641–648.

    CAS  Google Scholar 

  • Van Antwerp, D. J., Martin, S. J., Verma, I. M., and Green, D. R. (1998). Inhibition of TNF-induced apoptosis by NF-kB. Cell Biol 8, 107–111.

    Google Scholar 

  • van Hogerlinden, M., Rozell, B. L., Ahrlund-Richter, L., and Toftgard, R. (1999). Squamous cell carcinomas and increased apoptosis in skin with inhibited Rel/nuclear factor-kappaB signaling. Cancer Res 59, 3299–3303.

    Google Scholar 

  • Ventura, J. J., Cogswell, P., Flavell, R. A., Baldwin, A. S., Jr., and Davis, R. J. (2004). JNK potentiates TNF-stimulated necrosis by increasing the production of cytotoxic reactive oxygen species. Genes Dev 18, 2905–2915.

    CAS  Google Scholar 

  • Verschelde, C., Walzer, T., Galia, P., Biemont, M. C., Quemeneur, L., Revillard, J. P., Marvel, J., and Bonnefoy-Berard, N. (2003). A1/Bfl-1 expression is restricted to TCR engagement in T lymphocytes. Cell Death Differ 10, 1059–1067.

    CAS  Google Scholar 

  • Wang, C. Y., Mayo, M. W., and Baldwin, A. S., Jr. (1996). TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-kappaB. Science 274, 784–787.

    CAS  Google Scholar 

  • Wang, C. Y., Mayo, M. W., Korneluk, R. G., Goeddel, D. V., and Baldwin, A. S., Jr. (1998). NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c- IAP2 to suppress caspase-8 activation. Science 281, 1680–1683.

    CAS  Google Scholar 

  • Wertz, I. E., O’Rourke, K. M., Zhou, H., Eby, M., Aravind, L., Seshagiri, S., Wu, P., Wiesmann, C., Baker, R., Boone, D. L., Ma, A., Koonin, E. V., and Dixit, V. M. (2004). De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 430, 694–699.

    CAS  Google Scholar 

  • Wessendorf, S., Schwaenen, C., Kohlhammer, H., Kienle, D., Wrobel, G., Barth, T. F., Nessling, M., Möller, P., Döhner, H., Lichter, P., and Bentz, M. (2003). Hidden gene amplifications in aggressive B-cell non-Hodgkin lymphomas detected by microarray-based comparative genomic hybridization. Oncogene 22, 1425–1429.

    CAS  Google Scholar 

  • Wilkinson, J. C., Wilkinson, A. S., Scott, F. L., Csomos, R. A., Salvesen, G. S., and Duckett, C. S. (2004). Neutralization of Smac/Diablo by inhibitors of apoptosis (IAPs). A caspase-independent mechanism for apoptotic inhibition. J Biol Chem 279, 51082–51090.

    CAS  Google Scholar 

  • Wright, C. W. and Duckett, C. S. (2005). Reawakening the cellular death program in neoplasia through the therapeutic blockade of IAP function. J Clin Invest 115, 2673–2678.

    CAS  Google Scholar 

  • Wu, M., Arsura, M., Bellas, R. E., Fitzgerald, M. J., Lee, H., Schauer, S. L., Sherr, D. H., and Sonenshein, G. E. (1996). Inhibition of c-myc expression induces apoptosis of WEHI 231 murine B cells. Mol Cell Biol 16, 5015–5025.

    CAS  Google Scholar 

  • Xiang, H., Hochman, D. W., Saya, H., Fujiwara, T., Schwartzkroin, P. A., and Morrison, R. S. (1996). Evidence for p53-mediated modulation of neuronal viability. J Neurosci 16, 6753–6765.

    CAS  Google Scholar 

  • Xiao, G., Harhaj, E., and Sun, S. C. (2001). NF-kB-inducing kinase regulates the processing of NF-kB2 p100. Mol Cell 7, 401–409.

    CAS  Google Scholar 

  • Xiao, G., Fong, A., and Sun, S. C. (2004). Induction of p100 processing by NF-kappaB-inducing kinase involves docking IkappaB kinase alpha (IKKalpha) to p100 and IKKalpha-mediated phosphorylation. J Biol Chem 279, 30099–30105.

    CAS  Google Scholar 

  • Yamamoto, K. and Gaynor, R. B. (2001). Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest 107, 135–142.

    CAS  Google Scholar 

  • Yamamoto, Y., Yin, M. J., Lin, K. M., and Gaynor, R. B. (1999). Sulindac inhibits activation of the NF-kappaB pathway. J Biol Chem 274, 27307–27314.

    CAS  Google Scholar 

  • Yamazaki, T. and Kurosaki, T. (2003). Contribution of BCAP to maintenance of mature B cells through c-Rel. Nat Immunol 4, 780–786.

    CAS  Google Scholar 

  • Yan, M., Zhang, Z., Brady, J. R., Schilbach, S., Fairbrother, W. J., and Dixit, V. M. (2002). Identification of a novel death domain-containing adaptor molecule for ectodysplasin-A receptor that is mutated in crinkled mice. Curr Biol 12, 409–413.

    CAS  Google Scholar 

  • Yeh, W. C., Itie, A., Elia, A. J., Ng, M., Shu, H. B., Wakeham, A., Mirtsos, C., Suzuki, N., Bonnard, M., Goeddel, D. V., and Mak, T. W. (2000). Requirement for Casper (c-FLIP) in regulation of death receptor-induced apoptosis and embryonic development. Immunity 12, 633–642.

    CAS  Google Scholar 

  • Yin, M.-J., Yamamoto, Y., and Gaynor, R. B. (1998). The anti-inflammatory agents aspirin and salicylate inhibit the activity of IkB kinase-b. Nature 396, 77–80.

    CAS  Google Scholar 

  • Yu, Z., Zhou, D., Cheng, G., and Mattson, M. P. (2000). Neuroprotective role for the p50 subunit of NF-kappaB in an experimental model of Huntington’s disease. J Mol Neurosci 15, 31–44.

    CAS  Google Scholar 

  • Zeh, H. J., III and Lotze, M. T. (2005). Addicted to death: invasive cancer and the immune response to unscheduled cell death. J Immunother 28, 1–9.

    Google Scholar 

  • Zhang, J. Y., Tao, S., Kimmel, R., and Khavari, P. A. (2005). CDK4 regulation by TNFR1 and JNK is required for NF-kappaB-mediated epidermal growth control. J Cell Biol 168, 561–566.

    CAS  Google Scholar 

  • Zheng, L., Bidere, N., Staudt, D., Cubre, A., Orenstein, J., Chan, F. K., and Lenardo, M. (2006). Competitive control of independent programs of tumor necrosis factor receptor-induced cell death by TRADD and RIP1. Mol Cell Biol 26, 3505–3513.

    CAS  Google Scholar 

  • Zheng, Y., Ouaaz, F., Bruzzo, P., Singh, V., Gerondakis, S., and Beg, A. A. (2001). NF-kappa B RelA (p65) is essential for TNF-alpha-induced fas expression but dispensable for both TCR-induced expression and activation-induced cell death. J Immunol 166, 4949–4957.

    CAS  Google Scholar 

  • Zheng, Y., Vig, M., Lyons, J., Van Parijs, L., and Beg, A. A. (2003). Combined deficiency of p50 and cRel in CD4+ T cells reveals an essential requirement for nuclear factor kappaB in regulating mature T cell survival and in vivo function. J Exp Med 197, 861–874.

    CAS  Google Scholar 

  • Zhou, H., Wertz, I., O’Rourke, K., Ultsch, M., Seshagiri, S., Eby, M., Xiao, W., and Dixit, V. M. (2004). Bcl10 activates the NF-kappaB pathway through ubiquitination of NEMO. Nature 427, 167–171.

    CAS  Google Scholar 

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Fan, Y., Dutta, J., Gupta, N., Fan, G., Gélinas, C. (2008). Regulation of Programmed Cell Death by NF-κB and its Role in Tumorigenesis and Therapy. In: Programmed Cell Death in Cancer Progression and Therapy. Advances in Experimental Medicine and Biology, vol 615. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-6554-5_11

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