Key words: Rel; NF-kB; IkB; oncogenes; cancer; leukemia; lymphoma; cancer therapy; signal transduction; angiogenesis; metastasis; cell survival; amplification; proliferation

ABSTRACT
The Rel/NF-kB family is a group of structurally-related, tightly-regulated transcription factors that control the expression of a multitude of genes involved in key cellular and organismal processes. The Rel/NF-kB signal transduction pathway is misregulated in a variety of human cancers, especially ones of lymphoid cell origin, due either to genetic changes (such as chromosomal rearrangements, amplifications, and mutations) or to chronic activation of the pathway by epigenetic mechanisms. Constitutive activation of the Rel/NF-kB pathway can contribute to the oncogenic state in several ways, for example, by driving proliferation, by enhancing cell survival, or by promoting angiogenesis or metastasis. In many cases, inhibition of Rel/NF-kB activity reverses all or part of the malignant state. Thus, the Rel/NF-kB pathway has received much attention as a focal point for clinical intervention.

1. Introduction
The development of a highly malignant tumor requires numerous changes in cellular metabolism, including ones that affect proliferation, cell death (apoptosis), immune system recognition, adhesion, and angiogenesis. Thus, it is really no surprise that the Rel/NF-kB signal transduction pathway, which influences various aspects of cellular and organismal physiology, has emerged as playing a major role in many human cancers. In vertebrates, there are five major Rel/NF-kB transcription factors: RelA (or p65), RelB, c-Rel, p50/p105 (NF-kB1), and p52/p100 (NF-kB2). These proteins form almost all combinations of homodimers and heterodimers, which bind with high affinity to a rather broad array of related decameric sites, generically called kB sites (for review see Ref. [1]). The most common heterodimer in many cell types is composed of p50-RelA, and is specifically referred to as NF-kB. Rel/NF-kB transcription factors are related through a highly conserved, N-terminal DNA-binding/dimerization/nuclear targeting domain called the Rel Homology domain. One class of Rel protein (p105 and p100) contains C-terminal inhibitory domains that must be removed to create the active DNA-binding component (p50 and p52, respectively). The second class of Rel protein (RelA, RelB, c-Rel) contains C-terminal transcription activation domains, which are not removed. Thus, homodimers of p50 or p52 are often repressors of kB site-dependent transcription, whereas any dimers that contain RelA, RelB or c-Rel usually increase transcription.

In most cell types, the activity of Rel/NF-kB complexes is tightly regulated (for review see Ref. [2]). That is, the dimers are primarily in the cytoplasm, due to interaction with any of a family of inhibitors known as IkB proteins (IkBα, IkBβ, IkBe, Bcl-3, p100, p105). In the best-characterized example, IkBα interacts with NF-kB to keep the complex largely in the cytoplasm due to the strong nuclear export sequence of IkBα. A variety of extracellular signals and intracellular stresses can activate NF-kB (for review see Ref. [3]). Most of these signals act through the IkB kinase (IKK) complex (for review see Refs. [2,4]). The primary IKK complex is composed of three subunits: IKKα (a kinase), IKKβ (a kinase), and IKKg (an essential activating protein). Activation of IKK enables it to phosphorylate IkBα at 2 N-terminal serine residues, which leads to ubiquitination and degradation of IkBα by the proteasome. The liberated NF-kB is now largely a nuclear complex, which can bind to enhancers of target genes to usually activate their expression. One essential feature of this activation, however, is that it is normally transient, because one of primary target genes of NF-kB is the gene encoding IkBα. The NF-kB-induced and newly-synthesized IkBα can then remove NF-kB from DNA and can, within an hour or so in most cases, return the system to its resting, largely cytoplasmic state. Nevertheless, it is important to note that certain normal cell types, including mature B cells, have constitutively active, nuclear NF-kB.

2. The retroviral oncoprotein v-Rel
The first suggestion that Rel/NF-kB transcription factors would be involved in human cancers came from the study of the v-Rel oncoprotein encoded by the highly oncogenic avian Rev-T retrovirus (for review see Ref. [5]). v-Rel causes a rapidly fatal lymphoid cell malignancy in young chickens and can efficiently transform and immortalize a variety of chicken hematopoietic cell types in vitro. In most mammalian cell types, overexpression of v-Rel is toxic. However, when expressed in T cells in transgenic mice, v-Rel can induce T-cell lymphomas, albeit with a long latency [6].

v-Rel is approximately 50- to 100-fold more transforming than chicken c-Rel in vitro. v-Rel has a number of changes as compared to avian c-Rel, and many of these differences have functional consequences that contribute to the acute oncogenicity of v-Rel (for reviewe see Ref. [5]). For example, a large C-terminal deletion in v-Rel removes a transactivation domain, and the addition of retroviral envelope amino acids at the N terminus of v-Rel creates a transactivation domain. In addition, internal mutations in v-Rel reduce its ability to interact with IkBα, increase its stability, and change its DNA-binding site preference. The analysis of many v-Rel mutants indicates that v-Rel is oncogenic in avian lymphoid cells based on its ability to form homodimers, constitutively enter the nucleus, bind to DNA, and activate the transcription of a set of target genes that promote lymphoid cell proliferation and survival. As such, even though v-Rel has been selected during in vitro propagation for heightened oncogenicity, the general mechanism by which v-Rel transforms avian lymphoid cells is likely to serve as a model for how Rel/NF-kB activity contributes to human cancers.

3. Genetic associations of REL/NFKB and IKB genes with human cancers
Genetic alterations in REL/NFKB and IKB genes have been detected in a number of spontaneous human cancers and cell lines derived from human cancers (for review see Refs. [7,8]). These alterations include amplifications, chromosomal rearrangements, deletions, and point mutations (Table 1).

3.1 Gene amplifications
The REL gene, located at chromosomal position 2p16.1-15, is the REL/NFKB/IKB gene that has most consistently been found to be amplified in human cancers. In particular, REL amplifications are seen in non-Hodgkin’s B-cell lymphomas, including diffuse large B-cell lymphomas (DBCLs), follicular lymphomas, and mediastinal thymic B-cell lymphomas. Although the numbers can vary considerably among reports, REL amplification is likely to be present in up to 10-20% of these B-cell lymphomas and amplified in a range of 4- to 75-fold [9-16]. As damning to REL as these observations may be, it is important to note that there have been no strict correlations made between amplification of REL, overexpression of REL protein, expression of Rel/NF-kB target genes, and sensitivity to IkBα in any of these cases.

Much is now known about the overall mRNA expression patterns of DBCLs (for review see Ref. [17]). Based on cDNA microarray expression data, Alizadah et al [18] subdivided DBCLs into two subtypes: one with an expression pattern similar to germinal center B cells and one with an activated B cell-like expression pattern. Consistent with activation of the Rel/NF-kB pathway being important in the development of DBCL, a number of Rel/NF-kB target genes are overexpressed in the activated B cell-like class of DBCLs: these overexpressed genes include ones encoding cytokines, chemokines, anti-apoptotic factors, and Rel/NF-kB factors themselves [L.M. Staudt, pers. commun.]. Moreover, expression of a non-degradable super-repressor form of IkBα can block the growth of DBCL cells with the activated B cell-like expression pattern but not DBCLs with the germinal center B-cell expression pattern [L.M. Staudt, pers. commun.].

Taken together, the above-described findings indicate that increased REL protein expression contributes directly to the transformed state in many human lymphoid cancers, especially ones of B-cell origin. Moreover, we have recently demonstrated an oncogenic activity of human REL by showing that overexpressed wild-type human REL can malignantly transform and immortalize primary chicken lymphoid cells in culture [19]. Consistent with overexpression of REL being associated with B-cell malignancies, B cells from c-rel knockout mice do not proliferate in response to many mitogens and show increased apoptosis (for reviewe see Ref. [20]). That c-rel knockout mice are viable suggests that c-Rel is an apt molecular target for the treatment of certain human lymphoid cancers.

Because RELA and RELB, like REL, are strong activators of transcription, one might expect to find RELA or RELB to be amplified in human cancers. However, there have been only sporadic and largely unsubstantiated reports of amplification of RELA in human cancers and none of RELB amplification (for review see Ref. [7]); moreover, RELA or RELB have not been reported to transform cells in any in vitro system. Thus, REL appears to have a unique oncogenic ability among the transactivating Rel/NF-kB family members. The in vitro transforming ability of REL appears to reside in its DNA-binding domain [19], suggesting that increased activity of REL dimers (due to forced overexpression or gene amplification) leads to oncogenesis by affecting the expression of a specific set of genes, which are not targeted by RELA and RELB.

3.2 Chromosomal alterations
Chromosomal rearrangements that lead to the production of novel hybrid proteins are a hallmark of many hematopoeitic cell cancers (for review see Ref. [21]). In many cases, most notably the production of the BCR-ABL kinase in chronic myelogenous leukemia, these chimeric proteins drive the proliferation of the cancer and, as such, provide unique molecular targets. In a small number of human lymphoid cell cancers, rearrangements of the REL and NFKB2 genes lead to the production of C-terminally truncated REL and p100 proteins, respectively, or in other cases, to the overexpression of IkB-like protein BCL-3.

In the RC-K8 B-cell lymphoma cell line, a large deletion on chromosome 2 results in the expression of a hybrid protein, REL-NRG, which retains the REL DNA-binding domain fused to heterologous Non-Rel-Gene residues [9,22]. RC-K8 cells have nuclear complexes containing both wild-type REL and REL-NRG [D. Kalaitzidis and T.D. Gilmore, unpubl. results], and RC-K8 cells show increased expression of several Rel/NF-kB target genes [L.M. Staudt, pers. commun.]. However, there is no direct evidence that REL-NRG contributes to the malignant state of RC-K8 cells and REL-NRG has not been demonstrated to have transforming activity in vitro.

In several B- and T-cell lymphomas, chromosomal rearrangements or deletions involving chromosome 10 have resulted in loss of NFKB2 sequences encoding C-terminal sequences of p100 [23-26]. These truncated p100 proteins are constitutively nuclear [26,27], have increased transactivating ability as compared to either p100 or p52 [26-28], have decreased IkB activity [29], and may undergo unregulated processing (to p52) as compared to wild-type p100 [30]. Moreover, in at least one case, some of these truncated p100 proteins have been reported to be weakly oncogenic in mouse 3T3 cells [31]. Consistent with unchecked production of p52 contributing to oncogenesis, mice that constitutively express p52, due to a homozygous deletion of NFKB2 sequences encoding C-terminal sequences of p100, have increased numbers of T lymphocytes as well as gastric hyperplasia and enlarged lymph nodes [32]. Furthermore, White et al [33] have shown that p52-v-Rel heterodimers can transform avian lymphoid cells. Nevertheless, the lymphoma-derived p100 proteins have not themselves been directly shown to be oncogenic in any lymphoid cell transformation model. Although high levels of the related p50/p105 proteins are found in several tumors (for review see Ref. [7]), no genetic alterations of NFKB1 have yet been detected in human cancers.

The BCL-3 gene is on chromosome 19 and is located near the breakpoint of t(14:19) translocations that have been identified in several patients with B-cell chronic lymphocytic leukemia (for review see Ref. [34]). In general, these t(14:19) translocations place the switch region of the immunoglobulin heavy chain (from chromosome 14) 5’ to the BCL-3 gene (chromosome 19), and result in increased transcription of BCL-3. Although related to the IkB proteins, BCL-3 is a unique member in that it is largely a nuclear protein and can associate with p50 and p52 dimers to enhance transcription (for review Ref. [35]). Indeed, BCL-3 has attributes of a transcriptional co-activator [36]. As such, one would predict that overexpression of BCL-3 would result in increased transcription of genes normally regulated by p52 or p50 homodimers. Consistent with overexpression of BCL-3 contributing to human B-cell cancers, transgenic mice in which BCL-3 is overexpressed in B cells develop splenomegaly and show an excess of mature B cells in lymph nodes and bone marrow [37].

3.3 Mutations
The Reed-Sternberg (RS) cells of Hodgkin’s lymphoma are emerging as one of the clearest examples of a cancer of NF-kB dysregulation (for review see Ref. [38]). Both Hodgkin’s cell lines and primary disease tissues have constitutively active and nuclear NF-kB (p50-RELA and p50-REL complexes), and blockage of the NF-kB activity by overexpression of the super-repressor form of IkBα can lead to apoptosis in these cells [39-43]. In several of these Hodgkin’s disease cases, the increased nuclear NF-kB activity is a consequence of no IkBα being produced due to inactivating mutations in the IKBA gene [39,40,44]. In other cases, constitutive NF-kB activity is due to chronic signal-induced turnover of IkBα, perhaps due to secretion of an autocrine NF-kB-inducing factor by these cells [41,42]. Not surprisingly, a set of NF-kB target genes is overexpressed in RS cells, including those encoding antiapoptotic genes A1, c-IAP2, TRAF1, and Bcl-X_L, and growth promoting genes cyclin D2, CD86 and CD40 [43]. Thus, it is almost certain that chronic NF-kB activity is the cause of the enhanced survival of RS cells and probably also contributes to their proliferation.

There has been no systematic search for mutations in REL/NFKB/IKB genes in human cancers. However, in one myeloma, a point mutation in the RELA gene was detected [45]. This mutation results in a single amino acid change that reduces the DNA-binding and transactivating activity of RELA. However, it is not clear whether this mutation contributes to the transformed state of these cells.

4. Constitutive activation of Rel/NF-kB and human cancer
An accumulating set of data shows that a variety of human tumors and tumor cell lines have constitutively nuclear and active NF-kB DNA-binding activity (Table 2). In most cases, the activated kB site DNA-binding activity consists of p50-RELA dimers. That this constitutive NF-kB activity is relevant to some aspect of the tumor cell phenotype has generally been shown by inhibition of the activity by overexpression of a super-repressor form of IkBα. Such experiments have shown that constitutive NF-kB activity can contribute to the survival (i.e., anti-apoptosis) or growth of tumor cells [e.g., 39,46], tumor invasion and metastases [e.g., 47], and angiogenesis [47,48]. Thus, NF-kB may contribute to the control of different processes in different tumor cell types, much in the same way that NF-kB controls distinct cellular processes in different normal cell types.
However, some caution must be exercised in generalizing that inhibition of constitutively active p50-RELA will be an Achilles heel of all cancers. First, constitutive p50-RELA may, in some cases, be an adaptation of tumor cell lines to tissue culture. For example, Cogswell et al [49] reported that primary breast cancer specimens have active p52, c-Rel, and Bcl-3, whereas breast cancer cell lines have constitutively active RELA. Second, overexpression of the IkBα super-repressor actually promotes skin carcinomas in one transgenic mouse model system [50]. Thus, the growth and survival state of a given cell type may be controlled by a delicate balance in the activity of the Rel/NF-kB pathway.
Activation of NF-kB is also associated with virally-induced oncogenesis in humans. Namely, several human tumor viruses encode proteins that specifically activate the NF-kB signaling pathway and their ability to do so is usually associated with their oncogenicity. For example, the Tax oncoprotein of human T cell leukemia virus-1 activates NF-kB by interacting with the IKK complex [51], and the LMP-1 protein of Epstein-Barr virus acts as a constitutively active membrane receptor-like protein that persistently activates NF-kB through adaptor molecules that are ordinarily involved in tumor necrosis factor receptor signaling [52].

5. Anti-cancer therapy that targets NF-kB signaling

5.1 Natural and synthetic NF-kB inhibitors as anti-cancer agents
A variety of inhibitors of the NF-kB pathway may have a role in the prevention and treatment of cancer. Among natural compounds, curcumin, bees wax, green tea polyphenols, grape skin resvatrol, many fungal metabolites, and salicylic acid have long histories as anti-inflammatory and anti-cancer agents, and all can inhibit the induction of NF-kB (for reviews see Refs. [53,54]). Moreover, the preventative effects of aspirin against colon cancer may well involve inhibition of NF-kB [54]. However, as NF-kB is involved in many cellular processes, one suspects that some caution must be taken in following a regimen that would cause long-term diminution of NF-kB activity.

5.2 Directed inhibition of NF-kB and cancer therapy
Several chemotherapeutic agents induce NF-kB, which contributes to the unwanted survival of many tumor cells. Thus, agents that block induction of NF-kB sensitize tumor cells to such chemotherapeutic agents (for review see Ref. [55]). Consequently, there is great interest in developing novel, molecular inhibitors of the Rel/NF-kB pathway, as anti-inflammatory and anti-cancer agents (for review see Ref. [54]). To date, the problems with such inhibitors have been ones of delivery and specificity. For example, although the super-repressor form of IkBα can inhibit the growth of tumors in mouse model systems, it will probably not be a readily deliverable molecule in humans. Moreover, although potent and specific inhibitors of IKK have recently been identified [56], they may have unanticipated side effects in that IKK almost certainly will be found to regulate pathways in addition to NF-kB (e.g., Ref. [57]). Similarly, proteasome inhibitors are potent blockers of NF-kB activation and have shown promise as anti-cancer agents (for review see Ref. [58]), but obviously they affect many aspects of cell regulation. Thus, it seems that more useful inhibitors will target the individual Rel/NF-kB subunits or complexes that are dysregulated in specific cancers.

6. Conclusions
Activation of the Rel/NF-kB/IkB signal transduction pathway, either by mutation of specific family members or by chronic induction of the pathway, almost certainly contributes to the development or maintenance of a variety of human cancers. It is likely that the consequence of alteration of this pathway is the misguided activation of genes that control proliferation (e.g., cyclin D1), block apoptosis (e.g., FLIP, Bcl-Xl, Bcl-2, IAPs, TRAFs), and promote angiogenesis (e.g., VEGF). Nevertheless, there are few convenient mammalian model systems for studying the role of the Rel/NF-kB pathway in cancer in vivo or for detecting mutant genes in this pathway. Similarly, a large variety of natural and synthetic inhibitors of the Rel/NF-kB/IkB pathway have been identified, however, most of these inhibitors are still cumbersome or non-specific. As such, there will be continued interest in the development of in vivo models for Rel/NF-kB tumorigenesis and of potent and precise inhibitors of this pathway.

Acknowledgements
We thank L. Staudt (NIH) and S.-C. Sun (Penn State University Medical School) for helpful discussions. Work in our laboratory on Rel/NF-kB proteins and cancer is supported by NIH grant CA47763 (to T.D.G.). D.K. was partially supported by NIH predoctoral training grant T32-HD07387.

Table 1: Genetic associations of REL/NFKB/IKB genes with human cancers

Gene	Alteration
RELA	Mutation
RELB	None
REL	Amplification; chromosomal alteration
NFKB1	None
NFKB2	Chromosomal alteration
IKBA	Mutational inactivation
BCL3	Chromosomal rearrangement

Table 2: Constitutive activation of NF-kB in human cancer cells

Cancer type	Reference
Tumors and tumor cell lines
Breast	59,60
Ovary	48,61
Prostate	47,62,63
Kidney	64
Liver	65
Pancreas	66
Colon	67
Thyroid	68,69
Melanoma	70,71
Hodgkin’s lymphoma	39
Acute lymphoblastic leukemia	72
Acute myelogenous leukemia	73,74
Diffuse large B-cell lymphoma	*
Astrocytoma/glioblastoma	75
Head and neck	76,77
Vulva	78
In vitro transformation
BCR-ABL	79
DBL/DBS	80
RAF	81
RAS	82
TEL-JAK2	83
TEL-PDGFR	84
Viral oncogenesis
Epstein-Barr virus	52
Hepatitis B virus	85
Human Herpesvirus-8	86
Human T-cell leukemia virus-1	51

*L. Staudt, pers. commun.; D. Kalaitzidis & T.D. Gilmore, unpub. results.

References
[1] T.D. Gilmore, The Rel/NF-kB signal transduction pathway: introduction, Oncogene 18 (1999) 6842-6844.
[2] N. Silverman, T. Maniatis, NF-kB signaling pathways in mammalian and insect innate immunity, Genes Devel. 15 (2001) 2321-2342.
[3] H.L. Pahl, Activators and target genes of Rel/NF-kB transcription factors, Oncogene 18 (1999) 6853-6866.
[4] M. Karin, Y. Ben-Neriah, Phosphorylation meets ubiquitination: the control of NF-kB activity, Annu. Rev. Immunol. 18 (2000) 621-663.
[5] T.D. Gilmore, Multiple mutations contribute to the oncogenicity of the retroviral oncoprotein v-Rel, Oncogene 18 (1999) 6925-6937.
[6] D. Carrasco, C.A. Rizzo, K. Dorfman, R. Bravo, The v-rel oncogene promotes malignant T-cell leukemia/lymphoma in transgenic mice, EMBO J. 15 (1996) 3640-3650.
[7] B. Rayet, C. Gélinas, Aberrrant rel/nfkb genes and activity in human cancer, Oncogene 18 (1999) 6938-6987.
[8] T.D. Gilmore, J.-C. Epinat, M. Barkett, Misregulation of a signal transduction pathway: role of Rel/NF-kB transcription factors in oncogenesis, in: M. Ehrlich (Ed.), DNA Alterations in Cancer: Genetic and Epigenetic Changes, Eaton Publishing, Natick, MA, 2000, pp. 121-136.
[9] D. Lu, J.D. Thompson, G.K. Gorski, N.R. Rice, M.G. Mayer, J.J. Yunis, Alterations at the rel locus in human lymphoma, Oncogene 6 (1991) 1235-1241.
[10] J. Houldsworth, S. Mathew, P.H. Rao, K. Dyomina, D.C. Louie, N. Parsa, K. Offit, R.S.K. Chaganti, REL proto- oncogene is frequently amplified in extranodal diffuse large cell lymphoma, Blood 87 (1996) 25-29.
[11] S. Joos, J.I. Otaño-Joos, S. Ziegler, S. Brüderlein, S. du Manoir, M. Bentz, P. Möller, P. Lichter, Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene, Blood 87 (1996) 1571- 1578.
[12] T.F.E. Barth, H Döhner, C.A. Werner, S. Stilgenbauer, M. Schlotter, M. Pawlita, P. Lichter, P. Möller, M. Bentz, Characteristic pattern of chromosomal gains and losses in primary large B-cell lymphomas of the gastrointestinal tract, Blood 91 (1998) 4321-4330.
[13] P.H. Rao, J. Houldsworth, K. Dyomina, N.Z. Parsa, J.C. Cigudosa, D. C. Louie, L. Popplewell, K. Offit, S.C. Jhanwar, R.S.K. Chiaganti, Chromosomal and gene amplification in diffuse large B-cell lymphoma, Blood 92 (1998) 234-240.
[14] L.K. Goff, M.J. Neat, C.R. Crawley, L. Jones, E. Jones, T. A. Lister, R.K Gupta, The use of real-time quantitative polymerase chain reaction and comparative genomic hybridization to identify amplification of the REL gene in follicular lymphoma, Brit. J. Haematol. 111 (2000) 618-625.
[15] T.F. Barth, M. Bentz, F. Leithauser, S. Stilgenbauer, R. Siebert, M. Schlotter, R.F Schlenk, H. Döhner, P. Möller, Molecular-cytogenetic comparison of mucosa- associated marginal zone B-cell lymphoma and large B- cell lymphoma arising in the gastro-intestinal tract, Genes Chromosomes Cancer 31 (2001) 316-325.
[16] M.J. Neat, N. Foot, M. Jenner, L. Goff, K. Ashcroft, D. Burford, A. Dunham, A. Norton, T.A. Lister, J. Fitzgibbon, Localisation of a novel region of recurrent amplification in follicular lymphoma to an ~6.8 Mb region of 13q32-33, Genes Chromosomes Cancer 32 (2001) 236-243.
[17] R. Siebert, A. Rosenwald, L.M. Staudt, S.W. Morris, Molecular features of B-cell lymphoma, Curr. Opin. Oncol. 13 (2001) 316-324.
[18] A.A. Alizadeh, M.B. Eisen, R.E. Davis, C. Ma., I.S. Lossos, A. Rosenwald, J.C. Boldrick, H. Sabet, T. Tran, X. Yu, J.I. Powell, L. Yang, G.E. Marti, T. Moore, J. Hudson Jr., L. Lu, D.B. Lewis, T. Tibshirani, G. Sherlock, W.C. Chan, T.C. Greiner, D.D. Weisenburger, J.O. Armitage, R. Warnke, R. Levy, W. Wilson, M.R. Grever, J.C. Byrd, D. Botstein, P. O. Brown, L.M. Staudt, Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling, Nature 403 (2000) 503-511.
[19] T.D. Gilmore, C. Cormier, J. Jean-Jacques, M.-E. Gapuzan, Malignant transformation of primary chicken spleen cells by human transcription factor c-Rel, Oncogene (2001) in press.
[20] S. Gerondakis, M. Grossmann, Y. Nakamura, T. Pohl, R. Grumont, Genetic approaches in mice to understand Rel/NF-kB and IkB function: transgenics and knockouts, Oncogene 19 (1999) 6888-6895.
[21] S.K. Bohlander, Fusion genes in leukemia: an emerging network, Cytogenet. Cell Genet. 91 (2002) 52-56.
[22] D. Kalaitzidis, T.D. Gilmore, Genomic organization and expression of the rearranged REL proto-oncogene in B-cell lymphoma cell line RC-K8, Genes Chromsomes Cancer (2001) in review.
[23] A. Neri, C.-C. Chang, L. Lombardi, M. Salina, A.T. Malolo, R.S.K. Chaganti, R. Dalla-Favera, B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-kB p50, Cell 67 (1991) 1075-1087.
[24] A. Migliazza, L. Lombardi, M. Rocchi, D. Trecca, C.-C. Chang, R. Antonacci, N.S. Fracchiolla, P. Ciana, A.T. Maiolo, A. Neri, Heterogeneous chromosomal aberrations generate 3’ truncations of the NFKB2/lyt-10 gene in lymphoid malignancies, Blood 84 (1994) 3850- 3860.
[25] S. Thakur, H.-C. Lin, W.-T. Tseng, S. Kumar, R. Bravo, F. Foss, C. Gélinas, A.B. Rabson, Rearrangement and altered expression of the NFKB-2 in human cutaneous T-lymphoma cells, Oncogene 9 (1994) 2335-2344.
[26] J. Zhang, C.-C. Chang, L. Lombardi, R. Dalla-Favera, Rearranged NFKB2 gene in the HUT78 T-lymphoma cell line codes for a constitutively nuclear factor lacking transcriptional repressor functions, Oncogene 9 (1994) 1931-1937.
[27] C.-C. Chang, J. Zhang, L. Lombardi, A. Neri, R. Dalla- Favera, Rearranged NFKB-2 genes in lymphoid neoplasms code for constitutively active nuclear transactivators, Mol. Cell. Biol. 15 (1995) 5180-5187.
[28] J.-C.Epinat, D. Kazandjian, D.D. Harkness, S. Petros, J. Dave, D.W. White, T.D. Gilmore, Mutant envelope residues confer a transactivation function onto N- terminal sequences of the v-Rel oncoprotein, Oncogene 19 (2000) 599-607.
[29] K.E. Kim, C. Gu, S. Thakur, E. Viera, J.C. Lin, A.B. Rabson, Transcriptional regulatory effects of lymphoma-associated NFKB2/lyt10 protooncogenes, Oncogene 19 (2000) 1334-1345.
[30] G. Xiao, E.W. Harhaj, S.-C. Sun, NF-kB-inducing kinase regulates the processing of NF-kB2 p100, Mol. Cell 7 (2001) 401-409.
[31] P. Ciana, A. Neri, C. Cappellini, F. Cavallo, M. Pomati,C.-C. Chang, A.T. Maiolo, L. Lombardi, Constitutive expression of lymphoma-associated NFKB- 2/Lyt-10 proteins is tumorigenic in murine fibroblasts, Oncogene 14 (1997) 1805-1810.
[32] H. Ishikawa, D Carrasco, E Claudio, R.-P. Ryseck, R. Bravo, Gastric hyperplasia and increased proliferative responses of lymphocytes in mice lacking the COOH- terminal ankyrin domain of NF-kB2, J. Exp. Med. 186 (1998) 999-1014.
[33] D.W. White, G.A. Pitoc, T.D. Gilmore, Interaction of the v-Rel oncoprotein with NF-kB and IkB proteins: heterodimers of a transformation-defective v-Rel mutant and NF-kB p52 are functional in vitro and in vivo, Mol. Cell. Biol. 16 (1996) 1169-1178.
[34] T.W. McKeithan, G.S. Takimoto, H. Ohno, V.S. Bjorling, R. Morgan, B.K. Hecht, I Dubé, A.A. Sandberg, J.D. Rowley, BCL3 rearrangements and t(14;19) in chronic lymphocytic leukemia and other B-cell malignancies: a molecular and cytogenetic study, Genes Chromosomes Cancer 20 (1997) 64-72.
[35] M. Lenardo, U. Siebenlist, Bcl-3-mediated nuclear regulation of the NF-kB trans-activating factor, Immunol. Today 15 (1994) 145-147.
[36] R. Dechend, F. Hirano, K. Lehmann, V. Heissmeyer, S. Ansieau, F.G. Wulczyn, C. Scheidereit, A. Leutz, The Bcl-3 oncoprotein acts as a bridging factor between NF-kB/Rel and nuclear co-regulators, Oncogene 18 (1999) 3316-3323.
[37] S.T. Ong, M.L. Hackbarth, L.C. Degenstein, D.A. Baunoch, J. Anastasi, T.W. McKeithan, Lymphadenopathy, splenomegaly, and altered immunoglobulin production in BCL3 transgenic mice, Oncogene 16 (1998) 2333-2343.
[38] L.M. Staudt. The molecular and cellular origins of Hodgkin’s disease, J. Exp. Med. 191 (2000) 207-212.
[39] R.C. Bargou, F. Emmerich, D. Krappmann, K. Bommert, M.Y. Mapara, W. Arnold, H.D. Royer, E. Grinstein, A. Greiner, C. Scheidereit, B. Dörkin, Constitutive NF-kB- RelA activation is required for proliferation and survival of Hodgkin’s disease tumor cells, J. Clin. Invest. 100 (1997) 2961-2969.
[40] K.M. Wood, M. Roff, R.T. Hay, Defective IkBα in Hodgkin cell lines with constitutively active NF-kB, Oncogene 16 (1998) 2131-2139.
[41] F. Emmerich, M. Meiser, M. Hummel, G. Demel, H.D. Foss, F. Jundt, S. Mathas, D. Krappmann, C. Scheidereit, H. Stein, B. D&oulm;rken, Overexpression of IkBα without inhibition of NF-kB activity and mutations in the IkBα gene in Reed-Sternberg cells, Blood 94 (1999) 3129-3134.
[42] D. Krappmann, F. Emmerich, U. Kordes, E. Scharschmidt, B. Dörken, C. Scheidereit, Molecular mechanisms of constitutive NF-kB/Rel activation in Hodgkin/Reed Sternberg cells, Oncogene 18 (1999) 943-953.
[43] M. Hinz, P. Loser, S. Mathas, D. Krappmann, B. Dörken, C. Scheidereit, Constitutive NF-kB maintains high expression of a characteristic gene network, including CD40, CD86, and a set of antiapoptotic genes in Hodgkin/Reed-Sternberg cells, Blood 97 (2001) 2798-2807.
[44] B. Jungnickel, A. Staratscheck-Jox, A. Braunninger, T. Speiker, J. Wolf, V. Diehl, M.-L. Hansmann, K. Rajewsky, R. Kuppers, Clonal deleterious mutations in the IkBα gene in the malignant cells in Hodgkin’s lymphoma, J. Exp. Med. 191 (1999) 395-402.
[45] D. Trecca, L. Guerrini, N.S. Fracchiolla, M. Pomati, L. Baldini, A.T. Maiolo, A. Neri, Identification of a tumor-associated form of NF-kB RelA gene with reduced DNA-binding and transactivating activities, Oncogene 14 (1997) 791-799.
[46] D.C. Duffey, Z. Chen, G. Dong, F.G. Ondrey, J.S. Wolf, K. Brown, U. Siebenlist, C. Van Waes, Expression of a dominant- negative mutant inhibitor-kBα of nuclear factor-kB in human head and neck squamous cell carconoma inhibits survival, proinflammatory cytokine expression, and tumor growth in vivo, Cancer Res. 59 (1999) 3468-3474.
[47] S. Huang, C.A. Pettaway, H. Uehara, C.D. Bucana, I.J. Fidler, Blockade of NF-kB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis, Oncogene 20 (2001) 4188-4197.
[48] S. Huang, J.B. Robinson, A. DeGuzman, C.D. Bucana, I.J. Fidler, Blockade of nuclear factor-kB signaling inhibits angiogenesis and tumorigenicity of ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8, Cancer Res. 60 (2000) 5334-5339.
[49] P.C. Cogswell, D.C. Guttridge, W.K. Funkhouser, A.S. Baldwin Jr., Selective activation of NF-kB subunits in human breast cancer: potential roles for NF-kB2/p52 and for Bcl-3, Oncogene 19 (2000) 1123-1131.
[50] M. van Hogerlinden, B.L. Rozell, L. Ährlund-Richter, R. Toftgård, Squamous cell carcinomas and increased apoptosis in skin with inhibited Rel/nuclear factor-kB signaling, Cancer Res. 59 (1999) 3299-3303.
[51] K.T. Jeang, Functional activities of the human T-cell leukemia virus type I Tax oncoprotein: cellular signaling through NF-kB, Cytokine Growth Factor Rev. 12 (2001) 207-217.
[52] E.D. Cahir McFarland, K.M. Izumi, G. Mosialos, Epstein- Barr virus transformation: involvement of latent membrane protein 1-mediated activation of NF-kB, Oncogene 18 (1999) 6959-6964.
[53] J.-C. Epinat, T.D. Gilmore, Diverse agents act at multiple levels to inhibit the Rel/NF-kB signal transduction pathway, Oncogene 18 (1999) 6896-6909.
[54] Y. Yamamoto, R.B. Gaynor, Therapeutic potential of inhibition of the NF-kB pathway in the treatment of inflammation and cancer, J. Clin. Invest. 107 (2001) 135-142.
[55] A.S. Baldwin, Control of oncogenesis and cancer therapy resistance by the transcription factor, J. Clin. Invest. 107 (2001) 241-246.
[56] L. O’Neil, Inhibiting NF-kB, Trends Immunol. 22 (2001) 478.
[57] C. Lamberti, K.M. Kin, Y. Yamamoto, U. Verma, I.M. Verma, S. Byers, R.B. Gaynor, Regulation of b-catenin function by the IkB kinases, J. Biol. Chem. (2001) in press.
[58] J. Adams, V.J. Palombella, P.J. Elliott, Proteasome inhibition: a new strategy in cancer treatment, Invest. New Drugs 18 (2000) 109-121.
[59] H. Nakshatri, P. Bhat-Nakshatri, D.A. Martin, R.J. Goulet Jr., G.W. Sledge Jr., Constitutive activation of NF-kB during progression of breast cancer to hormone- independent growth, Mol. Cell. Biol. 17 (1997) 3629- 3639.
[60] M.A. Sovak, R.E. Bellas, D.W. Kim, G.J. Zanieski, A.E. Rogers, A.M. Traish, G.E. Sonenshein, Aberrant nuclear factor-kB/Rel expression and the pathogenesis of breast cancer, J. Clin. Invest. 100 (1997) 2952-2960.
[61] E. Dejardin, V. Deregowski, m Chapelier, N. Jacobs, J. Gielen, M.-P. Merville, V. Bours, Regulation of NF-kB activity by IkB-related proteins in adenocarcinoma cells, Oncogene 18 (1999) 2567-2577.
[62] F. Pajonk, K. Pajonk, W.H. McBride, Inhibition of NF-kB, clonogenicity, and radiosensitivity of human cancer cells, J. Natl. Cancer Inst. 91 (1999) 1956-1960.
[63] S.T. Palayoor, M.Y. Yourmell, S.K Calderwood, C.N. Coleman, B.D. Price, Constitutive activation of IkB kinase a and NF-kB in prostate cancer cells is inhibited by ibuprofen, Oncogene 18 (1999) 7389-7394.
[64] M. Oya, M. Ohtsubo, A. Takayanagi, M. Tachibana, N. Shimizu, M. Murai, Constitutive activation of NF-kB prevents TRAIL-induced apoptosis in renal cancer cells, Oncogene 20 (2001) 3888-3896.
[65] D.L. Tai, S.L. Tsai, Y.H. Chang, S.N. Huang, T.C. Chen, K.S. Chang, Y.F. Liaw, Constitutive activation of nuclear factor kB in hepatocellular carcinoma, Cancer 89 (2000) 2274-2281.
[66] W. Wang, J.L. Abbruzzese, D.B. Evans, L. Larry, K.R. Cleary, P.J. Chiao, The NF-kB RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells, Clin. Cancer Res. 5 (1999) 119-127.
[67] D.S. Lind, S.N. Hochwald, J. Malaty, S. Rekkas, P. Hebig, G. Mishra, L.L Moldwawer, E.M. Copeland III, S. Mackay, Nuclear factor-kB is upregulated in colorectal cancer, Surgery 130 (2001) 363-369.
[68] R. Visconti, R., J. Cerutti, S. Battista, M. Fedele, F. Trapasso, K. Zeki, M.P. Miano, F. de Nigris, L. Casalino, F. Curcio, M. Santoro, A. Fusco, Expression of the neoplastic phenotype by human thyroid carcinoma cell lines requires NFkB p65 protein expression, Oncogene 15 (1997) 1987-1994.
[69] L. Ludwig, H. Kessler, M. Wagner, C. Hoang-Vu, H. Dralle, G. Adler, B.O. Bohm, R.M. Schmid, Nuclear factor-kB is constitutively active in C-cell carcinoma and required for RET-induced transformation, Cancer Res. 61 (2001) 4526-4535.
[70] F.L. Meyskens Jr., J.A. Buckmeier, S.E. McNulty, N.B. Tohidian, Activation of nuclear factor-kB in human metastatic melanoma cells and the effect of oxidative stress, Clin. Cancer Res. 5 (1999) 1197-1202.
[71] J. Yang, A. Richmond, Constitutive IkB kinase activity correlates with nuclear factor-kB activation in human melanoma cells, Cancer Res. (2001) 61 4901-4909.
[72] U. Kordes, D. Krappmann, V. Heissmeyer, W.D. Ludwig, C. Scheidereit, Transcription factor NF-kB is constitutively active in acute lymphoblastic leukemia cells, Leukemia 14 (2000) 399-402.
[73] W.H Dokter, L. Tuyt, S.J. Sierdsema, M.T. Esselink. E. Vellenga, The spontaneous expression of interleukin-1β and interleukin-6 is associated with spontaneous expression of AP-1 and NF-kB transcription factor in acute myeloblastic leukemia cells, Leukemia, 9 (19995) 425-432.
[74] M.L. Guzman, S.J. Neering, D. Upchurch, B. Grimes, D.S. Howard, D.A. Rizzieri, S.M. Luger, C.T Jordan, Nuclear factor-kB is constitutively activated in primitive human acute myelogenous leukemia cells, Blood 98 (2001) 2301-2307.
[75] S. Hayashi, M. Yamamoto, Y. Ueno, K. Ikeda, K. Ohshima, G. Soma, T. Fukushima, Expression of nuclear factor-kB, tumor necrosis factor receptor type 1, and c-Myc in human astrocytomas, Neurol. Med. Chir. 41 (2001) 187-195.
[76] F.G. Ondrey, G. Dong, J. Sunwoo, Z. Chen. J.S. Wolf, C.V. Crowl-Bancroft, N. Mukaida, C. Van Waes, Constitutive activation of transcription factors NF-kB, AP-1, and NF-IL6 in human head and neck squamous cell carcinoma cell lines that express pro-inflmammatory and pro-angiogenic cytokines, Mol. Carcinog. 26 (1999) 119- 129.
[77] T. Tamatani, M Azuma, K. Aota, T. Yamashita, T. Bando, M. Sato, Enhanced IkB kinase activity is responsible for the augmented activity of NF-kB in human head and neck carcinoma cells, Cancer Lett. 171 (2001) 165-172.
[78] M. Seppanen, K.K. Vihko, Activation of transcription factor NF-kB by growth inhibitory cytokines in vulvar carcinoma cells, Immunol. Lett. 74 (2000) 103-109.
[79] J.Y. Reuther, G.W. Reuther, D. Cortez, A.M. Pendergast, A.S. Baldwin Jr., A requirement for NF-kB activation in Bcr-Abl- mediated transformation, Genes Devel. 12 (1998) 968-981.
[80] I.P. Whitehead, Q.T. Lambert, J.A. Glaven, K. Abe, K.L. Rossman, G.M. Mahon, J.M. Trzaskos, R. Kay, S.L. Campbell, C.J. Der, Dependence of Dbl and Dbs transformation on MEK and NF-kB activation, Mol. Cell. Biol. 19 (1999) 7759-7770.
[81] B. Baumann, C.K. Weber, J. Troppmair, S. Whiteside, A. Israël, U.R Rapp, T. Wirth, Raf induces NF-kB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation, Proc. Natl. Acad. Sci. USA 97 (2000) 4615-4620.
[82] T.S. Finco, J.K. Westwick, J.L. Norris, A.A. Beg, C.J. Der, A.S. Baldwin Jr., Oncogenic Ha-Ras-induced signaling activates NF-kB transcriptional activity, which is required for cellular transformation, J. Biol. Chem. 272 (1997) 24113-24116.
[83] S.C. Santos, R. Monni, I. Bouchaert, O. Bernard, S. Gisselbrecht, F. Gouilleux, V. Penard-Lacronique, Involvement of the NF-kB pathway in the transforming properties of the TEL-Jak2 leukemogenic fusion protein, FEBS Lett. 497 (2001) 148-152.
[84] F. Besancon, A. Atfi, C. Gespach, Y.E. Cayre, M.F. Bourgeade, Evidence for a role of NF-kB in the survival of hematopoietic cells mediated by interleukin-3 and the oncogenic TEL/platelet-derived growth β fusion protein, Proc. Natl. Acad. Sci. USA 95 (1998) 8081-8086.
[85] J. Diao, R. Garces, C.D. Richardson, X protein of hepatitis B virus modulates cytokine and growth factor related signal transduction pathways during the course of viral infections and hepatocarcinogenesis, Cytokine Growth Factor Rev. 12 (2001) 189-205.
[86] S. Pati, M. Cavrois, H.G. Guo, J.S. Foulke Jr., J. Kim, R.A. Feldman, M. Reitz, Activation of NF-kB by the human herpesvirus 8 chemokine receptor ORF74: evidence for a paracrine model of Kaposi’s sarcoma pathogenesis, J. Virol. 75 (2001) 8660-8673.

Back . . .