[en] The well-known Rel/NF-kappaB family of vertebrate transcription factors comprises a number of structurally related, interacting proteins that bind DNA as dimers and whose activity is regulated by subcellular location. This family includes many members (p50, p52, RelA, RelB, c-Rel, ...), most of which can form DNA-binding homo- or hetero-dimers. All Rel proteins contain a highly conserved domain of approximately 300 amino-acids, called the Rel homology domain (RH), which contains sequences necessary for the formation of dimers, nuclear localization, DNA binding and IkappaB binding. Nuclear expression and consequent biological action of the eukaryotic NF-kappaB transcription factor complex are tightly regulated through its cytoplasmic retention by ankyrin-rich inhibitory proteins known as IkappaB. The IkappaB proteins include a group of related proteins that interact with Rel dimers and regulate their activities. The interaction of a given IkappaB protein with a Rel complex can affect the Rel complex in distinct ways. In the best characterized example, IkappaB-alpha interacts with a p50/RelA (NF-kappaB) heterodimer to retain the complex in the cytoplasm and inhibit its DNA-binding activity. The NF-kappaB/IkappaB-alpha complex is located in the cytoplasm of most resting cells, but can be rapidly induced to enter the cell nucleus. Upon receiving a variety of signals, many of which are probably mediated by the generation of reactive oxygen species (ROS), IkappaB-alpha undergoes phosphorylation at serine residues by a ubiquitin-dependent protein kinase, is then ubiquitinated at nearby lysine residues and finally degraded by the proteasome, probably while still complexed with NF-kappaB. Removal of IkappaB-alpha uncovers the nuclear localization signals on subunits of NF-kappaB, allowing the complex to enter the nucleus, bind to DNA and affect gene expression. Like proinflammatory cytokines (e.g. IL-1, TNF), various ROS (peroxides, singlet oxygen, ...) as well as UV (C to A) light are capable of mediating NF-kappaB nuclear translocation, while the sensor molecules which are sensitive to these agents and trigger IkappaB-alpha proteolysis are still unidentified. We also show that a ROS-independent mechanism is activated by IL-1beta in epithelial cells and seems to involve the acidic sphingomyelinase/ceramide transduction pathway.
Baeuerle, P.A. (1991). The inducible transcription factor NF-κB-regulation by distinct protein subunits. Biochim. Biophys. Acta. 1072, 63-80.
Baeuerle, P.A., and Henkel, T. (1994). Function and activation of NF-κB in the immune system. Annu. Rev. Immunol. 12, 141-179.
Baldi, L., Brown, K., Franzoso, G., and Siebenlist, U. (1996). Critical role for lysines 21 and 22 in signal-induced, ubiquitin-mediated proteolysis of IκB-α. J. Biol. Chem. 271, 376-379.
Basu-Modak, S., Lüscher, R, and Tyrrell, R.M. (1996). Lipid metabolite involvement in the activation of the human heme oxygenase-1 gene. Free Rad. Biol. Med. 20, 887-897.
Beg, A.A., and Baldwin, A.S. (1993). The IκB proteins: multifunctional regulators of Rel/NF-κB transcription factors. Genes Dev. 7, 2064-2070.
Beg, A.A., Finco, T.S., Nantermet, P.V., and Baldwin, A.S. (1993). Tumor necrosis factor and interleukin 1 lead to phosphorylation and loss of IκBα-a mechanism for NF-κB activation. Mol. Cell. Biol. 13, 3301-3310.
Bender, K., Blattner, C., Knebel, A., lordanov, M., Herrlich, P., and Rahmsdorf, H.H. (1997). UV-induced signal transduction. J. Photochem. Photobiol. B. 37, 1-17.
Bonizzi, G., Dejardin, E., Piret, B., Piette, J., Merville, M.P., and Bours, V. (1996). IL-1β induces NF-κB in epithelial cells independently of the production of reactive oxygen intermediates. Eur. J. Biochem. 142, 544-549.
Bonizzi, G., Piette, J., Merville, M.P., and Bours, V. (1997). Distinct signal transduction pathways mediate NF-κB induction by IL-1b in epithelial and lymphoid cells. J. Immunol., in press.
Brach, M.A., Haas, R., Sherman, M.L., Gunji, H., Weichselbaum, R., and Kufe, D. (1991). Ionizing radiation induces expression and binding activity of the nuclear factor kappa B. J. Clin. Invest. 88, 691-695.
Brown, K., Gersterberger, S., Carlson, L., Franzoso, G.,and Siebenliestt, U. (1995). Control of IκBα proteolysis by site-specific, signal induced phosphorylation. Science 267, 1485-1488.
Chen, Z.J., Hagler, J., Palombella, J., Melandri, F., Scherer, D., Ballard, D., and Maniatis, T. (1995). Signal-induced site-specific phosphorylation targets IκBα to the ubiquitin-proteasome pathways. Genes Dev 9, 1586-1597.
Chen, Z.J., Parent, L., and Maniatis, Y. (1996). Site-specific phosphorylation of IκBα by a novel ubiquitination-dependent protein kinase activity. Cell 84, 853-862.
Cordle, S.R., Donald, R., Read, M.A., and Hawiger, J. (1993). Liposaccharide induces phosphorylation of MAD3 and activation of C-rel and related NF-κB proteins in human monocytic THP-1 cells. J. Biol. Chem. 268, 11803-11810.
Devary, Y., Gottlieb, R.A., Smeal, T., and Karin, M. (1992). The mammalian ultraviolet response is triggered by activation of src tyrosine kinases. Cell 71, 1081-1112.
Devary, Y., Rosette, C., DiDonato, J.A., and Karin, M. (1993). NF-κB activation by ultraviolet light does not depend on a nuclear signal. Science 261, 1442-1445.
DiDonato, J.A., Mercurio, F., and Karin, M. (1995). Phosphorylation of IκBα precedes but is not sufficient for its dissociation from NF-κB. Mol. Cell. Biol. 15, 1302-1311.
DiDonato, J.A., Mercurio, F., Rosette, C., Wu-Li, J., Suyan, H., Ghosh, S., and Karin, M. (1996). Mapping of the inducible IkB phosphorylation sites that signal its ubiquitination and degradation. Mol. Cell. Biol. 16, 1295-1304.
Dujardin, E., Bonizzi, G., Bellahcène, A., Castronovo, V., Merville, M.P., and Bours, V. (1995). Highly-expressed p100/p52 (NFKB2) sequesters other NF-κB-related proteins in the cytoplasm of human breast cancer cells. Oncogene 11, 1835-1841.
Finco, T.S., Beg, A.A., and Baldwin, A.S., Jr. (1994). Inducible phosphorylation of IκBα is not sufficient for its dissociation from NF-κB and is inhibited by protease inhibitors. Proc. Natl. Acad. Sci. USA 91, 11884-11888.
Friedberg, E., Walker, G., and Siede, W. (1995). DNA Repair and Mutagenesis. (Washington, DC., USA: ASM Press)
Froelich-Ammon, S.J., and Osheroff, N. (1995). Topoisomerase poisons: harnessing the dark side of enzyme mechanism. J. Biol. Chem. 270, 21429-21432.
Granstein, R.D. (1996). Cytokines and photocarcinogenesis. Photochem. Photbiol. 63, 390-394.
Grilli, M., Chiu, J.J.-S., and Lenardo, M.J. (1993). NF-κB and relparticipants in a multiform transcriptional regulatory system. Int. Rev. Cytol. 143, 1-62.
Hayashi, T., Sekine, T., and Okamoto, T. (1993). Identification of a new serine kinase that activates NF-κB by direct phosphorylation. J. Biol. Chem. 268, 26790-26795.
Hayashi, T., Ueno, Y., and Okamoto, T. (1993). Oxidoreductive regulation of NF-κB. Involvement of a cellular reducing catalyst thioredoxin. J. Biol. Chem. 268, 11380-11388.
Herrlich, P., and Rahmsdorf, H.J. (1994). Transcriptional and post-transcriptional responses to DNA-damaging agents. Curr. Opinion Cell. Biol. 6, 425-431.
Herrlich, P., Ponta, H., and Rahmsdorf, H.J. (1992). DNA-damage induced gene expression: signal transduction and relation to growth factor signaling. Rev. Physiol. Biochem. Pharmacol. 119, 187-223.
Herrlich, P., Sachsenmaier, C., Radler-Pohl, A., Gebel, S., Blattner, C., and Rahmsdorf, H.J. (1994). The mammalian UV response (Mechanism of DNA damage induced gene expression). In: Advances in Enzyme Regulation, Vol. 34, G. Weber, ed. (Oxford, UK: Pergamon Press), pp. 381-395.
Holbrook, N.J., and Fornace, A.J. (1991). Response to adversity: molecular control of gene activation following genotoxic stress. New Biol. 3, 825-833.
Imbert, V., Rupee, R.A., Livolsi, A., Pahl, H.L., Traenckner, E.B.-M., Mueller-Dieckmann, C., Farahifar, D., Rossi, B., Auberger, P., Baeuerle, P.A., and Peyron, J.F. (1996). Tyrosine phosphorylation of IκB-α activates NF-κB without proteolytic degradation of IκB-α. Cell 86, 787-798.
Israel, A. (1995). A role for phosphorylation and degradation in the control of NF-κB activity. Trends Genet. 11, 203-205.
Jaffrézou, J.-P., Levade, T., Bettaïeb, A., Andrieu, N., Bezombes, C., Maestre, N., Vermeersch, S., Rousse, A., and Laurent, G. (1996). Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis. EMBO J. 15, 2417-2424.
Kanno, T., Franzoso, G., and Siebenliest, U. (1994). Human T-cell leukemia virus type 1 tax-protein-mediated activation of NF-κB from p100 (NF-kB2)-inhibited cytoplasmic reservoirs. Proc. Natl. Acad. Sci. USA 91, 12634-12638.
Kretz-Remy, C., Mehle, P., Mirault, M.-E., and Arroge, A.-P. (1996). Inhibition of IkB-alpha phosphorylation and degradation and subsequent NF-kB activation by glutathione peroxidase overexpression. J. Cell. Biol. 133, 1083-1093.
Kripke, M., Cox, P., Alas, L., and Yarosh, D. (1992). Pyrimidine dimers in DNA initiate systemic immunosuppression in UV-irradiated mice. Proc. Natl. Acad. Sci. USA 89, 7516-7620.
Legrand-Poels, S., Hoebeke, M., Vaira, D., Rentier, B., and Piette, J. (1993). HIV-1 promoter activation following an oxidative stress mediated by singlet oxygen. J. Photochem. Photobiol. B. 17, 229-237.
Legrand-Poels, S., Bours, V., Piret, B., Pflaum, M., Epe, B., Rentier, B., and Piette, J. (1995). Transcription factor NF-κB is activated by photosensitization generating oxidative DNA damages. J. Biol. Chem. 270, 6925-6934.
Lin, Y-C., Brown, K., and Siebenlist, U. (1995). Activation of NF-κB requires proteolysis of the inhibitor IκBα: signal induced phosphorylation of IκBα alone does not release active NF-κB. Proc. Natl. Acad. Sci. USA 92, 3003-3009.
Little, J.W., and Mount, D.W. (1982). The SOS regulatory system of Escherichia coli. Cell 29, 11-22.
Mai, S., Stein, B., van den Berg, S., Kaina, B., Lücke-Huhle, C., Ponta, H., Rahmsdorf, H.J., Kraemer, M., Gebel, S., and Herrlich, P. (1989). Mechanisms of the ultraviolet response in mammalian cells. J. Cell. Science 94, 609-615.
Miyamoto, S., and Verma, I.M. (1995). Rel/NF-κBIκB story. Adv. Cancer Res. 66, 255-292.
Miyamoto, S., Maki, M., Schmitt, M.J., Hatanaka, M., and Verma, I.M. (1994). Tumor necrosis factor a-induced phosphorylation of IκBα is a signal for its degradation but not dissociation from NF-κB. Proc. Natl. Acad. Sci. USA 91, 12740-12744.
O'Connor, A., Nishigori, C., Yarosh, D., Alas, L., Kibitel, J., Burley, L., Cox, P., Bucana, C., Ullrich, S., and Kripke, M. (1996). DNA double stranded breaks in epidermal cells cause immune suppression in vivo and cytokine production in vitro. J. Immunol. 157, 271-278.
Pathak, M.A., and Carbonare, M.D. (1990). Reactive oxygen species in photoaging and biochemical studies in the amelioration of photoaging changes. In: Biological Responses to Ultraviolet A Irradiation, F. Urbach (Kansas: Valdenmar Publishing Company), pp. 189-207.
Pearce, A.D., Gaskell, S.A., and Marks, R. (1987). Epidermal changes in human skin following irradiation with either UVB or UVA. J. Invest. Dermatol. 88, 83-87.
Pentland, A.R (1996). Signal transduction mechanisms in photocarcinogenesis. Photochem. Photobiol. 63, 379-380.
Piette, J., Merville, M.P., and Decuyper, J. (1985). Damages induced in nucleic acids by photosensitization. Photochem. Photobiol. 44, 793-802.
Piret, B., and Piette, J. (1996). Topoisomerase poisons activate the transcription factor NF-kappaB in ACH-2 and CEM cells. Nucleic Acids Res. 24, 4242-4248.
Piret, B., Legrand-Poels, S., Sappey, C., and Piette, J. (1995). NF-κB transcription factor and human immunodeficiency virus type 1 (HIV-1) activation by methylene blue photosensitization. Eur. J. Biochem. 228, 447-455.
Povirk, L.F., and Austin, M.J.F. (1991). Genotoxicity of bleomycin. Mutation Res. 257, 127-143.
Reelfs, O.S., and Tyrrell, R.M. (1995). Nuclear factor KB activation by UVA radiation. In: 6th Congress of the European Society for Photobiology (Cambridge, UK), p. 103.
Renard, P., Zachari, M.-D., Bougelet, C., Mirault, M.-E., Haegeman, G., Remade, J., and Raes, M. (1997). Effects of antioxidant enzymes modulations on interleukin-1-induced NF-κB activation. Biochem. Pharmacol. 53, 149-160.
Rodriguez, M.S., Wright, J., Thompson, J., Thomas, D., Baleux, F., Virelizier, J.-L., Hay, R.T., and Arenzana-Seisdedos, F. (1996). Identification of lysine residues required for signal-induced ubiquitination and degradation of IκB-α in vivo. Oncogene 12, 2425-2435.
Sachsenmaier, C., Rahler-Pohl, A., Müller, A., Herrlich, P., and Rahmsdorf, H.J. (1994). Damage to DNA by UV light and activation of transcription factors. Biochem. Pharmacol. 47, 129-136.
Sappey, C., Legrand-Poels, S., Best-Belpomme, M., Favier, A., Rentier, B., and Piette, J. (1994). Stimulation of glutathione peroxidase activity decreases HIV type 1 activation after oxidative stress. AIDS Res. Hum. Retroviruses. 10, 1451-1461.
Schenk, H., Klein, M., Erdbürger, W., Droge, W., and Schultze-Osthoff, K. (1994). Distinct effects of thioredoxin and other antioxidants on the activation of NF-κB and AP-1. Proc. Natl. Acad. Sci. USA 91, 1672-1676.
Scherer, D.C., Brockman, J.A., Chen, Z., Maniatis, T., and Ballard, D.W. (1995). Signal-induced degradation of IκBα requires site-specific ubiquitination. Proc. Natl. Acad. Sci. USA 92, 11259-11263.
Schmidt, K.N., Amstad, P., Cerutti, P., and Baeuerle, P.A. (1995). The roles of hydrogen peroxide and superoxide as messengers in the activation of transcription factor NF-κB. Chem. Biol. 2, 13-22.
Schnurr, K., Belkner, J., Ursini, F., Schewe, T., Kühn, H. (1996). The selenoenzyme phospholipid hydroperoxide glutathione peroxidase controls the activity of the 15-lipoxygenase with complex substrates and preserves the specificity of the oxygenation products. J. Biol. Chem. 271, 4653-4658.
Schoonbroodt, S., Legrand-Poels, S., Best-Belpomme, M., and Piette, J. (1997). Hypochlorous acid activates NF-κB transcription factor in T lymphocytes. Biochemical J. 321, 777-785.
Schreck, R., Rieber, P., and Baeuerle, P.A. (1991). Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-κB transcription factor and HIV-1. EMBO J. 10, 2247-2258.
Schreck, R., Meier, B., Mannel, D.N., Droge, W., and Baeuerle, P.A. (1992a). Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J. Exp. Med. 175, 1181-1194.
Schreck, R., Albermann, K., and Baeuerle, P.A. (1992b). Nuclear factor kappa B: an oxidative stress-responsive transcription factor of eukaryotic cells (a review). Free Rad. Res. Commun. 17, 221-227.
Schütz, S., Potthoff, K., Machleidt, T., Berkovic, D., Wiegmann, K., and Krönke, M. (1992). TNF activates NF-κB by phosphatidylcholine-specific phospholipase C-induced 'acidic' sphingomyelin breakdown. Cell 71, 765-776.
Siebenlist, U., Franzoso, G., and Brown, K. (1994). Structure, regulation and function of NF-κB. Annu. Rev. Cell. Biol. 10, 405-455.
Simon, M.M., Aragane, Y., Schwarz, A., Luget, T.A., and Schwarz, T. (1993). UV-B light induces nuclear factor κB (NF-κB) activity independently from chromosomal DNA damage in cell-free cytosolicextracts. J. Invest. Dermatol. 102, 422-427.
Singh, S., Darnay, B.G., and Aggarwal, B.B. (1996). Site-specific tyrosine phosphorylation of IκBα negatively regulates its inducible phosphorylation and degradation. J. Biol. Chem. 271, 31049-31054.
Slater, A.F.G., Kimland, M., Jiang, S.A., and Orrenius, S. (1995). Constitutive nuclear NF-κB/Rel DNA-binding activity of rat thymocytes is increased by stimuli that promote apoptosis, but not inhibited by pyrrolidine dithiocarbamate. Biochem. J. 312, 833-838.
Stein, B., Krämer, M., Rahmsdorf, H.J., Ponta, H., and Herrlich, P. (1989). UV-induced transcription from the Human Immunodeficiency Virus type 1 (HIV-1) Long Terminal Repeat and UV-induced secretion of an extracellular factor that induces HIV-1 transcription in nonirradiated cells. J. Virol. 63, 4540-4544.
Sun, S.-C., Elwood, J., Greene, W.C. (1996). Both amino- and carboxy-terminal sequences within IκBα regulate its inducible degradation. Mol. Cell. Biol. 16, 1058-1065.
Thanos, D., and Maniatis, T. (1995). NF-κB: a lesson in family values. Cell 80, 529-532.
Traenckner, E.B.M., Pahl, H.L., Henkel, T., Schmidt, S., Wilk, S., and Baeuerle, P.A. (1995). Phosphorylation of human IκBα on serines 32 and 36 controls IκBα protreolysis and NF-κB activation in response to diverse stimuli. EMBO J. 14, 5433-5441.
Tyrrell, R.M. (1996a). Oxidant, antioxidant status and photocarcinogenesis: the role of gene activation. Photochem. Photobiol. 63, 380-383.
Tyrrell, R.M. (1996b). Activation of mammalian gene expression by the UV component of sunlight: from models to reality. Bioessays 18, 139-148.
Valerie, K., and Rosenberg, M. (1990). Chromatin structure implicated in activation of HIV-1 gene expression by ultraviolet light. New Biol. 2, 712-718.
Valerie, K., Singhal, A., Kirckham, J.C., Laster, W.S., and Rosenberg, M. (1995). Activation of human immunodeficiency virus gene expression by ultraviolet light in stably transfected human cells does not require the enhancer element. Biochemistry 34, 15760-15767.
Van Antwerp, D. J., and Verma, I.M. (1996). Signal-induced degradation of IκBα: association with NF-κB and the PEST sequence in IκBα are not required. Mol. Cell. Biol. 16, 6037-6045.
Verma, I.M., Stevenson, J.K., Schwarz, E.M., Van Antwerp, D., and Miyamoto, S. (1995). Rel/NF-κB/IκB family: Intimate tales of association and dissociation. Genes Dev. 9, 2723-2735.
Vile, G.T., and Tyrrell, R.M. (1995). UVA radiation-induced oxidative damage to lipids and proteins in vitro and in human skin fibroblasts id dependent on iron and singlet oxygen. Free Rad. Biol. Med. 18, 721-730.
Vile, G.T., Tanew-Iliitschew, A., andTyrrell, R.M.(1995). Activation of NF-κB in human skin fibroblasts by the oxidative stress generated by UVAradiation. Photochem. Photobiol. 62, 436-468.
Warso, M.A., and Lands, W.E. (1985). Presence of lipid hydroperoxide in human plasma. J. Clin. Invest. 15, 667-671.
Weinstein, I.B. (1988). The origins of human cancer: Molecular mechanisms of carcinogenesis and their implications for cancer prevention and treatment. Cancer Res. 48, 4135-4143.
Weitzel, F., and Wendel, A. (1993). Selenoenzymes regulate the activity of leukocyte 5-lipoxygenase via the peroxide tone. J. Biol. Chem. 268, 6288-6292.
Wolf, P., Yarosh, D., and Kripke, M. (1993). Effects of sunscreens and a DNA excision repair enzyme on ultraviolet radiation-induced inflammation, immune suppression, and cyclobutane pyrimidine dimer formation in mice. J. Invest. Dermatol. 101, 523-527.
Yarosh, D.B., Alas, L., Kibitel, J., O'Connor, A., Carrier, F., Fornace, A.J. (1993). Cyclobutane pyrimidine dimers in UV-DNA induce release of soluble mediators that activate the human immunodeficiency virus promoter. J. Invest. Dermatol. 100, 790-794.
