Leukemia (2002) 16, 1053–1068  2002 Nature Publishing Group All rights reserved 0887-6924/02 $25.00 www.nature.com/leu SPOTLIGHT REVIEW Nuclear transcription factor-B as a target for cancer drug development A Garg and BB Aggarwal Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Nuclear factor kappa B (NF-B) is a family of inducible tran- scription factors found virtually ubiquitously in all cells. Since its discovery by Sen and Baltimore in 1986, much has been discovered about its mechanisms of activation, its target genes, and its function in a variety of human diseases including those related to inflammation, asthma, atherosclerosis, AIDS, septic shock, arthritis, and cancer. Due to its role in a wide variety of diseases, NF-B has become one of the major targets for drug development. Here, we review our current knowledge of NF-B, the possible mechanisms of its activation, its poten- tial role in cancer, and various strategies being employed to target the NF-B signaling pathway for cancer drug develop- ment. Leukemia (2002) 16, 1053–1068. DOI: 10.1038/sj/leu/2402482 Keywords: nuclear factor kappa B (NF-B); IB kinase (IKK); inflammation; cancer; drug development; apoptosis Introduction Transcription is an important regulatory event in the pathway leadingtogeneexpression.Transcriptionfactorsregulatetran- scription by binding to specific sequences present within the promoter,enhancer,orotherregulatoryregionsofDNA.Hun- dreds of transcription factors with functionally separable domains,essentialforDNA-bindingandactivation,havebeen identified and characterized in several organisms. 1 One such transcription factor, NF-B, has been the subject of intense study based on the implications of its role as a key mediator of a wide variety of cellular responses. 2 Nuclear Factor B NF-B was first identified in the nuclei of mature B lympho- cytes as a transcription factor that binds an 11-bp DNA sequence in the -light chain enhancer GGGACTTTCC. 3 Mammalian cells have five distinct NF-B subunits based on a highly conserved 300 amino acid dimerization domain calledtherelhomologydomain,whichisrequiredforbinding DNAandmediatingthetranscriptionofover180targetgenes. These subunits may be classified into two functional groups, one containing the NF-B1 (p105/p50) and NF-B2 (p100/p52) subunits and the other containing the RelA (p65), RelB,andc-Relsubunits.Membersofthesecondgroupshare a carboxy-terminal transactivation domain usually required withintheRel/NF-Bstructuretopromotetranscription.Mem- bers of the first group exist as precursor subunits p105 and p100 (105000 and 100000 daltons), which contain a series of five to seven ankyrin repeat domains that mask the nuclear Correspondence: BB Aggarwal, Cytokine Research Laboratory, Department of Bioimmunotherapy, Box 143, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA; Fax: 713-794-1613 Received 19 September 2001; accepted 21 January 2002 localization signals (NLS) within the rel homology domain. They must be cleaved to the active p50 and p52 subunits (from p105 and p100, respectively) before allowing the trans- location of the NF-B complex from the cytoplasm to the nucleus, where transcription takes place. Other inhibitory subunits that utilize a similar ankyrin repeat domain (but do not contain the rel homology domain ofthefivesubunitsabove)includeIB (mostcommon),IkB, IkB (derivedfromtheC-terminalofp100),IkB-,Bcl-3,pp40 (chicken homologue), and avian swine fever virus protein p28.2. More recently, another IB-like subunit called IkB-, with six ankyrin repeat domains, was discovered and was found to retain the NF-B proteins in the nucleus instead of the cytoplasm. 4 There are several different structural combinations of sub- units in the cytoplasm that are called NF-B, with the most common heterodimer consisting of a Rel A subunit (p65), a NF-B1 subunit (p105/p50), and the IB inhibitory subunit. 5 On activation, degradation of IB exposes nuclear localiz- ation signals (NLS) on the p50-p65 heterodimer, leading to nuclear translocation and binding to a specific sequence in the DNA, which in turn results in gene transcription. This pathway is well conserved, both in structure and function, from Drosophila to humans. 6 How is NF-B activated? AlothasbeenlearnedaboutNF-Bactivationinthelastdec- ade. Cellular responses to a wide variety of diverse stimuli havebeenidentified,andhaveshowntoleadtotheactivation of NF-B (see Figure 1). These stimuli reveal that NF-Bisa common pathway for cellular adaptation to stress. 2,7,8 The stimuliincludeinflammatorycytokines,immune-relatedstress such as bacterial infection of S. aureus 9 and their products such as lipopolysaccharide 3 (or LPS), viruses such as HIV-1 10 and their products such as hemagglutinin of the flu virus, 11 physiologic stress such as ischemia, 12,13 physical stress such as UV irradiation, 14 environmental hazards such as cigarette smoke, 15 many therapeutic drugs such as taxol 16 or haloperi- dol, 17 apoptotic mediators such as anti-Fas, 18 growth factors such as insulin, 19 physiologic mediators such as angiotensin II 20 or PAF, 21,22 oxidative stress such as exposure to hydrogen peroxide, 23 and many more (see Figure 1). Depending on the stimulus, the mechanism of activation involvesoverlappingandnonoverlappingsteps.Amongallthe stimuli, perhaps the most is known about the mechanism by which TNF activates NF-B. This pathway involves the inter- actionoftheligandwithitsreceptoratthecellsurface(TNFR), which then recruits a protein called TNF receptor-associated death domain (TRADD). This protein binds to TNF receptor-associated factor (TRAF)-2, which activates receptor- interacting protein (RIP). RIP interacts with mitogen-activated protein kinase kinase kinase 3 (MEKK3) to phosphorylate and