Molecular Basis of Oncogenesis by NF-κB: From a Bird's Eye View to a RELevant Role in Cancer

Yongjun Fan; Jui Dutta; Nupur Gupta; Céline Gélinas

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

Cover of Madame Curie Bioscience Database

Madame Curie Bioscience Database [Internet].

Show details

Contents

< Prev Next >

Molecular Basis of Oncogenesis by NF-κB: From a Bird's Eye View to a RELevant Role in Cancer

Yongjun Fan, Jui Dutta, Nupur Gupta, and Céline Gélinas.

Author Information and Affiliations

The Rel/NF-κB transcription factors are renowned for their fundamental contribution to normal immune, inflammatory and acute phase responses. A growing body of evidence also underscores their important role in the control of cellular gene expression, cell proliferation and apoptosis. Thus, it comes as no surprise that sustained Rel/NF-κB activity has emerged as a hallmark of many human cancers. Experimental evidence indicates a strong correlation between the transcriptional activity of Rel/NF-κB and its role in malignant cell transformation. The important role of NF-κB in the control of the apoptotic response also supports its participation in the resistance of tumor cells to therapeutic treatment. This review focuses on the mechanisms that underlie the contribution of Rel/NF-κB to cancer and highlights how appreciation of its role in this context has evolved from a bird's eye view to a true recognition of its RELevant function in oncogenesis.

Introduction

The Rel/NF-κB transcription factors have been the focus of numerous studies aimed at elucidating their role in the development and function of the immune system and at unveiling the signaling pathways that control their activity (see accompanying chapters by M. Karin, S.C. Sun, R. Sen, U. Siebenlist, HC. Liou, Y. Chen, and C. Hunter). In recent years, there has been considerable progress in appreciating their contribution to oncogenesis and in understanding the mechanisms involved. Inappropriate Rel/NF-κB activity is observed in many different types of human cancers. Hyperactivation of the NF-κB signaling cascade, mutations that inactivate the inhibitory IκB subunits or chromosomal aberrations involving various rel/nf- κb genes have been noted in many human tumors.¹^,² Consistent with the transforming activity of the viral Rel/NF-κB oncoprotein v-Rel and its cellular homologue c-Rel in primary cells and in animal models, NF-κB is also critically involved in malignant cell transformation by viruses such as the human T-cell leukemia virus type I (HTLV-1) and Epstein-Barr virus (EBV).³ Collectively, these findings justify the vast body of literature exploring the molecular basis for the role of Rel/NF-κB in cancer. Important findings center on its ability to regulate cellular gene expression, to affect cell proliferation and survival, and on important regulatory mechanisms that control its activity — all of which have important consequences for effective anti-cancer therapy.⁴^-⁷

Constitutive Rel/NF-κB Activity Is a Hallmark of Many Human Cancers

Sustained activation of NF-κB is a feature of many human leukemia, lymphoma and solid tumors.¹ Immunohistochemistry, gel mobility shift assays and gene expression profiling of primary tumor specimens and tumor-derived cell lines have highlighted the persistent nuclear localization of NF-κB subunits compared to normal controls (for example see refs. 8-11). The dimer comprised of the p50/p65 subunits is the most frequently reported NF-κB complex to be activated in human cancer, although there is evidence that clearly implicates c-Rel-containing complexes in certain tumor types, like breast cancer.⁸^,⁹ The important implication of sustained NF-κB activity for the survival and proliferation of tumor cells is underscored by the growth arrest and rapid onset of apoptosis observed in many tumor-derived cell lines upon introduction of a degradation-resistant form of IκB (IκB super-repressor) to inhibit endogenous NF-κB activity (for example see refs. 12, 13).

Activation of the NF-κB Signaling Cascade

Persistent activation of the NF-κB pathway is observed in many different human cancers. By virtue of its ability to trigger the N-terminal phosphorylation of the NF-κB inhibitory subunit IκBα on serines 32 and 36, the IKK kinase complex promotes degradation of IκB via the ubiquitin/proteasome pathway. This enables NF-κB dimers to accumulate in the nucleus where they promote transcription of specific gene programs.¹⁴ Although the detailed mechanisms responsible for sustained IKK activation in many human tumors remain unknown, there are several potential mechanisms (Table 1).¹⁵^,¹⁶

Table 1

Mechanisms for constitutive NF-κB activation in human cancer.

IKK Complex Activation

Since no mutation has yet been identified to affect IKK subunits in human tumors, unrelenting activation of NF-κB is likely to result from alterations in upstream signaling components. In many types of cancer, sustained IKK activation is achieved via autocrine loops involving cytokines and growth factors that activate the NF-κB pathway and are themselves transcriptional targets of NF-κB (Tables 1, 2).¹⁷ For instance, IL-1 activates NF-κB in pancreatic carcinoma cell lines and is in turn induced by NF-κB.¹⁸ Likewise CD40, the receptor for CD40 ligand, constitutively activates NF-κB in malignant Reed-Sternberg (H/RS) cells of Hodgkin's disease (HD) and is upregulated in these cells.¹⁹ Another mechanism for constitutive ctivation of the IKK complex involves deregulation of TRAF adaptor proteins in human tumors. TRAF2 is a critical component of receptor-triggered signaling pathways involving NF-κB, JNK and p38. Recent work showed that loss of the TRAF2- and IKKγ/NEMO-interacting tumor suppressor protein CYLD, a de-ubiquitinating enzyme for TRAF2, leads to constitutive activation of IKK coincident with increased cell resistance to apoptosis.²⁰^-²³ Loss of CYLD causes cylindromatosis, an autosomal dominant syndrome that predisposes patients to benign tumors of hair follicles and sweat and scent glands.

Table 2

A sample of NF-κB-regulated gene products implicated in human cancer.

Interestingly, recent work unveiled a new NF-κB-independent role for IKK in cancer. IKKβ expression in primary breast cancer specimens is correlated with poor survival and studies in primary breast cancer cell lines showed that IKK negatively regulates the forkhead transcription factor FOXO3a, independent of NF-κB activation.²⁴ Indeed, IKK-mediated phosphorylation of FOXO3a promoted its nuclear export and proteolysis via the ubiquitin proteasome pathway to promote cell growth and tumorigenesis. It will be interesting to see if the newly reported abilities of IKKα and IKKγ/NEMO to localize to the nucleus and respectively modify histones and interact with CBP to regulate NF-κB gene expression imply that these subunits can also act on other nuclear targets to affect oncogenesis.²⁵^-²⁷

Activation by Other Kinases, Oncogenes and Viruses

Other means to constitutively activate NF-κB signaling in human tumors entail various kinases other than IKK, as well as oncogenes and viruses (Table 1). One example involves the PI3-kinase to Akt kinase signaling pathway in response to overexpression of the epidermal growth factor (EGF) receptor family member c-erbB2/Her-2/Neu in breast cancer.²⁸ IκBα degradation in this context is mediated by the protease calpain. Another example is casein kinase II (CKII) that phosphorylates serines in IκBα distinct from those targeted by IKK and triggers calpain-mediated cleavage of IκBα.²⁹ Upregulation of CKII activity was suggested as a possible contributing factor to hepatocarcinoma induced by TGF-β1.³⁰

A number of oncogenes mediate their transforming function by virtue of NF-κB activation. These include the chimeric oncoprotein tyrosine kinase Bcr-Abl implicated in acute lymphocytic leukemia (ALL) and chronic myelogenous leukemia (CML), and the Ras oncogene. Bcr-Abl enhances nuclear translocation of NF-κB and the transactivation function of NF-κB subunit p65/RelA via MEKK1 and p38 MAPK and also partially requires Ras function.³¹^-³³ Ras is another well-known oncogene mutated in human tumors that utilizes NF-κB to achieve oncogenesis.³⁴^,³⁵ The anti-oncogenic effect of lysyl oxidase on Ras-transformed cells was recently demonstrated to involve suppression of NF-κB activation.³⁶ An interesting new report showed that the API2/MALT1, a chimeric protein between inhibitor of apoptosis c-IAP2 and the MALT1 paracaspase, participates in the transformation process of mucosa-associated lymphoid tissue (MALT) lymphoma by activating NF-κB dimers comprised of RelB/p50.³⁷ It will be interesting to see whether other oncogenes act in a similar manner.

Lastly, many viruses achieve their oncogenic effects via the NF-κB signaling cascade (Table 1). A notable example relevant to human cancer is the human T-cell leukemia virus-1 (HTLV-1) implicated in acute T-cell leukemia (ATL). Persistent activation of NF-κB by HTLV-1 Tax causes nuclear accumulation of NF-κB dimers, helps to overcome their inhibition by the p105/ NF-κB1 subunit, and is an essential step in the transformation of T cells.³⁸^-⁴¹ Additionally, Tax stimulates phosphorylation-dependent processing of NF-κB2/p100, and hence activates both the canonical and noncanonical NF-κB pathways.⁴² Another virus that contributes to human cancer via NF-κB is the Epstein-Barr virus (EBV) implicated in Burkitt's and Hodgkin's lymphomas. The EBV nuclear antigen (EBNA)-2 and latent membrane protein (LMP)-1 enhance NF-κB activity thereby preventing apoptosis in EBV-transformed B cells.⁴¹^,⁴³ This is consistent with the ability of LMP-1 to induce expression of NF-κB-dependent anti-apoptotic proteins such as Bfl-1/A1.⁴⁴^,⁴⁵ Akin to Tax, LMP-1 induces proteolytic processing of p100/ NF-κB2 to its p52 form, consistent with the high levels of p52 found in Hodgkin's lymphoma and nasopharyngeal carcinoma from EBV-infected patients.⁴⁶^,⁴⁷

iκB Gene Mutations

Although much less frequent than upstream activation of the NF-κB pathway, there have been a few reports of iκB gene mutations implicated in constitutively activating NF-κB in human tumors. Mutations that suppress the inhibitory activity of IκBα or IκBε were observed in some Hodgkin's lymphomas and a large B-cell lymphoma cell line (Table 1).⁴⁸^-⁵³ The fact that bi-allelic mutation was needed for IκBα loss-of-function in Hodgkin's lymphoma raised the suggestion that it may act as a tumor suppressor.

nf-κB Gene Rearrangement, Amplification and/or Overexpression in Human Cancer

While sustained activation of NF-κB signaling is the most common mode of NF-κB activation in human tumors, there are a number of cases in which rel/nf-κB gene amplification, rearrangement and/or overexpression was documented (Table 1).¹ The majority of human rel and nf-κB genes (i.e., c-rel, relA, nf-κb1 and nf-κb2) have been targeted in this fashion, although nf-κb2 and c-rel are the most commonly affected.

Chromosomal rearrangements disrupting the 3' coding region of the nf-κb2 gene are frequently observed in cutaneous T-cell lymphoma and also in a small number of B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia and multiple myeloma.⁵⁴^-⁵⁸ The resulting C-terminally truncated p100/NF-κB2 proteins primarily localize to nuclei and bind to NF-κB DNA motifs. However, how tumor-derived truncated p100 proteins contribute to oncogenesis remains to be clarified. Loss of the C-terminal ankyrin motifs in tumor-derived p100 mutants was proposed to abolish the IκB-like function of p100, resulting in abnormal NF-κB activity. A more recent study suggested another mechanism for oncogenic activation, i.e., that loss of a putative C-terminal death domain in tumor-derived p100 mutants might abrogate a proapoptotic effect of p100,⁵⁹ although this has been a subject of debate.⁶⁰ It is interesting to note that homozygous deletion of the C-terminal ankyrin repeats of p100 leads to gastric and lymph node hyperplasia in mice, suggesting that overexpression of p52/NF-κB2 contributes to oncogenesis.⁶¹^-⁶³ In support of this hypothesis, tumor-derived rearranged p100 proteins undergo constitutive processing to produce functional p52, due to deletion of a C-terminal processing-inhibitory domain (PID).⁶⁴ Moreover, overexpression of p52 was detected in several malignancies including T-cell leukemia and breast and colon carcinoma.⁹^,⁶⁵^,⁶⁶ The ability of p52 homodimers to function as transcriptional activators in combination with RelB or the IκB-related Bcl-3 transcription factor to promote expression of antiapoptotic and proproliferative genes such as bcl-2 and cyclin D1 is consistent with this model.⁹^,⁶⁷

The human c-rel locus is amplified in a significant proportion of diffuse lymphoma with a large cell component (DLLC; 23%) and also in primary mediastinal (thymic) B-cell lymphoma, classical Hodgkin's lymphoma and certain follicular large cell lymphoma.¹ However, the extent to which c-rel gene amplification causes elevated nuclear c-Rel protein levels is unclear. While some found a correlation between amplification of the c-rel locus and nuclear c-Rel protein accumulation in Hodgkin's lymphoma and mediastinal large B-cell lymphoma (MLBCL),⁶⁸^,⁶⁹ others found no close association between the two or with NF-κB target gene expression profiles in diffuse large B cell lymphoma (DLBCL).⁷⁰^,⁷¹ These findings suggest that if c-rel plays a role, its function may be heterogeneous in different lymphomas or that it might play a role early in the history of some of these tumors that is no longer required later on. Although c-rel's contribution to some of these tumors remains a point of contention,⁷² future studies will undoubtedly provide important information on the subject.

Molecular Basis for Oncogenesis by Rel/NF-κB

Studies with the retroviral NF-κB oncoprotein v-Rel and its cellular Rel/NF-κB homologues have provided important insights into the oncogenic properties of Rel/NF-κB factors and the functional mechanisms involved. These are reviewed in this section.

The Viral NF-κB Oncoprotein v-Rel: A Potent Transforming Factor

Evidence pointing to a role for Rel/NF-κB in cancer came about long before the discovery of the rel/nf-κb gene family, with the isolation in 1958 of the Rev-T retrovirus from the liver of a diseased turkey.⁷³^,⁷⁴ The culprit Rev-T-encoded oncogene was identified many years later as v-rel, the first member of the Rel/NF-κB family.⁷⁵ v-rel immortalizes and transforms immature and mature B and T lymphoid, myeloid and dendritic cells from chicken spleen and bone marrow and induces aggressive and fatal leukemia/lymphoma in infected young birds.⁷⁶^-⁷⁹ v-Rel can also transform chicken embryo fibroblasts that induce tumors in immunocompetent young chicks.⁸⁰

The oncogenic activity of v-rel was believed for some time to be restricted to avian species, as efforts to stably express it in rodent fibroblasts or lymphoid B cells resulted in apparent cytotoxicity.⁸¹^-⁸³ Although the molecular basis for this effect remains to be clarified, stable expression was recently achieved in mouse fibroblasts using a mouse stem cell virus (MSCV),⁸⁴ but it remains to be seen if MSCV-driven v-rel will be transforming in mouse lymphoid cells. Yet, the discovery that transgenic mice expressing v-rel under the control of the lck promoter developed aggressive T-cell leukemia/lymphoma provided unambiguous proof of its oncogenic potential in mammals.⁸⁵ It is noteworthy however that the onset of tumor development in transgenic mice is remarkably slower than in infected chickens, with mice succumbing between 6 to 10 months of age compared to 7 to 10 days in young chicks. Another distinction between the avian and mammalian systems is the fact that tumors arising in v-rel transgenic mice are oligoclonal, rather than polyclonal in nature, and that they fail to transplant in syngeneic animals.⁸⁵ This suggests that additional cytogenetic alterations are necessary for manifestation of v-rel's tumorigenic potential in mammals. In this regard, chickens lack p16^INK4a and express a truncated but functional ARF protein.⁸⁶ This raises the possibility that tumor suppressors such as those encoded by the ink4b-arf-ink4a locus perhaps contribute to the increased susceptibility of chickens to v-rel-induced transformation. Nevertheless, in light of the rapidly increasing number of studies implicating Rel/NF-κB activity in human tumors, v-rel is a highly prized tool to unravel the molecular basis for the oncogenic activity of cellular Rel/ NF-κB factors.

A Role for c-Rel in Cell Transformation and Tumorigenesis: Lessons from Birds and Mice

Since v-rel arose by recombination of the non-transforming Rev-A retrovirus with the turkey c-rel proto-oncogene, it is not surprising to find that overexpression of the chicken, mouse or human c-rel genes transforms primary chicken cells in culture that induced tumor development in animal models, albeit at a lower efficiency than v-rel.⁸⁷^-⁹¹ However when tested under similar conditions, other mammalian Rel/NF-κB subunits namely RelA, RelB, p50/NF-κB1 or p52/NF-κB2 failed to transform lymphoid cells.⁸⁷ Together, these findings suggest that overexpression of the c-Rel protein in some tumors showing c-rel gene amplification and/or constitutive activation of c-Rel-containing NF-κB complexes might contribute to certain human leukemia/lymphoma.

Importantly, c-rel was recently shown to also exhibit an oncogenic capacity in a mammalian system. Indeed, 31% of transgenic mice expressing the mouse c-rel gene under the control of the mouse mammary tumor virus (MMTV) promoter developed mammary tumors at an average age of 19.9 months.⁹² Tumor development coincided with nuclear localization of NF-κB subunits and upregulation of many NF-κB-target genes including cyclin D1, c-myc, and bcl-xl (Table 2; see below). The significance of these findings is highlighted by the fact that many human breast cancer specimens show elevated NF-κB activity.⁸^,⁹^,⁹³^-⁹⁵

Rel/NF-κB Functions Necessary for Cell Transformation

As a result of its acquisition and evolution in the context of the Rev-T retrovirus, v-rel encodes a truncated and mutated version of the turkey c-Rel protein fused to remnants of the Rev-A retroviral env gene. v-Rel carries a number of deletions and point mutations compared to c-Rel, including the loss of 118 C-terminal amino acids that correspond to a strong transactivation domain (TAD) in c-Rel.⁷⁴ Many of these differences contribute to the increased oncogenicity of v-Rel compared to c-Rel. For example selection for C-terminal truncation of c-Rel, reminiscent of that seen in v-Rel, was observed in tumors that arose following retroviral-mediated delivery of c-rel into young chickens.⁹⁶ Recent work from our group indicates that c-rel gene deletion or mutation is not necessary for lymphoid cell transformation “per se”, but that it may rather be selected for during tumor progression to confer enhanced tumorigenicity, enable escape from immune surveillance and/or facilitate cell adaptation to growth in culture.⁸⁷

A model for v-Rel-mediated oncogenesis has emerged that invokes its ability to transactivate κB site-dependent gene transcription as being critical for cell transformation. Mutations that decrease its DNA-binding or transactivation functions are detrimental to cell transformation, whereas those that increase these activities enhance its transforming potential.⁹⁷^-¹⁰⁶ Consistent with this model, v-Rel shuttles between the nucleus and the cytoplasm, and a threshold of nuclear v-Rel is necessary to transform cells.¹⁰⁷ Other factors also contribute to the enhanced oncogenicity of v-Rel compared to c-Rel.⁷⁴ These include the fact that: (1) v-Rel is less susceptible than c-Rel to inhibition by IκBα.¹⁰⁸^,¹⁰⁹ This agrees with the partial nuclear distribution of v-Rel/IκBα complexes compared to predominantly cytoplasmic NF-κB/IκBα complexes in unstimulated cells.¹¹⁰^,¹¹¹ Despite its reduced susceptibility to inhibition by IκBα, v-Rel is nevertheless subject to IκBα control, as overexpression of IκBα in v-rel transgenic mice attenuated its tumorigenic phenotype.¹¹² (2) v-Rel binds to a broader range of NF-κB DNA sites compared to c-Rel and other NF-κB subunits. Nehyba et al identified mutation clusters in v-Rel responsible for this difference, and Phelps and Ghosh recently pinpointed amino acid differences between the Rel-homology domains (RHDs) of v-Rel and c-Rel in this effect.¹⁰⁹^,¹¹³ (3) The particular dimers in which v-Rel participates also dictate its oncogenic potential. Mutational analysis revealed a critical role for v-Rel homodimers in cell transformation.¹¹⁴ Although v-Rel/p50 heterodimers and v-Rel homodimers are the major DNA-binding complexes in v-rel transgenic mice, transgenic expression of v-rel in a p50 knockout background led to a more aggressive tumor phenotype.⁸⁵ (4) Recent work from our group indicated that critical determinants for the different oncogenic potentials of individual Rel/NF-κB subunits reside within their divergent TADs.⁸⁷ While RelA fails to transform primary chicken spleen cells, substitution of its TAD by that of the transforming v-Rel or c-Rel proteins conferred a strong transforming phenotype both in vitro and in vivo. Intrinsic differences between individual Rel/NF-κB TADs might confer distinct oncogenic potentials owing to differences in the repertoire of genes that they activate, as suggested by preliminary microarray analyses (Gupta, Fan, Delrow and Gélinas, unpublished data). Furthermore, the strength of individual Rel/NF-κB TADs is inversely correlated with their transforming potential, indicating that the magnitude of gene activation must be within a suitable range. For example, deletion of either of the two human c-Rel TADs reduced its transcriptional activity and increased its transforming efficiency.¹¹⁵ Since strong TADs such as that of RelA perhaps activate gene expression to a level that is incompatible with cell transformation, it is tempting to speculate that RelA mutants with decreased transactivation potency might be capable of transformation. Preliminary data from our group suggest that this may indeed be the case (Fan and Gélinas, unpublished data). Overall, these findings underscore a fundamental role for gene transactivation in the transforming ability of Rel/NF-κB.

Functional Consequences of Rel/NF-κB-Mediated Gene Activation in Oncogenesis

The Rel/NF-κB transcription factors activate a wide variety of target genes that influence its oncogenicity. These include cell death inhibitors, cell cycle regulators, transcription factors and oncoproteins, cytokines and receptors, and cell surface and adhesion molecules. This section reviews how these contribute to the transformation process by affecting the regulation of apoptosis, cell proliferation, angiogenesis and metastasis.

Suppression of Apoptosis

Escape from apoptosis is a major factor in oncogenesis and in the resistance of tumor cells to therapy. It is therefore not surprising that NF-κB's anti-apoptotic activity has been linked to many different cancers and that it impedes effective treatment.¹¹⁶^, ¹¹⁷ Consistent with the fact that Rel/NF-κB inhibits cell death by activating expression of antiapoptotic genes that can at least partially substitute for NF-κB to suppress cell death, many tumor-derived cell lines display elevated expression of NF-κB-dependent antiapoptotic factors (Table 2).⁴ For instance, therapy-resistant DLBCL tumors and malignant H/RS cells have elevated levels of bfl-1/a1 transcripts compared to controls, and FLIP is upregulated in DLBCL while c-iap2 is induced in H/RS cells.¹¹^, ¹⁹^, ⁷¹^, ¹¹⁸ The important role for NF-κB in these cancers is highlighted by the fact that many tumor-derived cell lines, including those derived from HD, DLBCL and breast cancer undergo spontaneous apoptosis, or are sensitized to death-inducing stimuli, following NF-κB inhibition (for example see refs. 6,8,12,13,119-121). Although ectopic expression of Bcl-xL could rescue apoptosis of H/RS cells in which NF-κB activity was suppressed,¹⁹ it should be noted that in other cases multiple apoptosis inhibitors appear to act in concert to promote survival in NF-κB-associated tumors.¹² These findings agree with the observation that sustained expression of v-rel is necessary to maintain the viability of transformed lymphoid cells and that v-rel-mediated transformation requires expression of specific apoptosis inhibitors (Table 2).¹⁰⁰^,¹⁰⁶^,¹²²^-¹²⁷ Though a majority of studies emphasize a fundamental role for the cytoprotective activity of NF-κB in oncogenesis, there are exceptions. For instance, survival in Bcr-Abl-induced leukemia was reported to be independent of NF-κB's antiapoptotic activity.³¹

Alternative mechanisms have emerged in which NF-κB promotes cell viability by interacting with other factors. For example, NF-κB interferes with the transcriptional function of the pro-apoptotic tumor suppressor p53 by competing for coactivators.¹²⁸^-¹³⁰ Similarly, p65/RelA sequesters coactivator p300 to inhibit expression of tumor suppressor PTEN and allow cell survival in lung and thyroid cancer cells.¹³¹ The recently discovered capacity of IKKβ to increase expression of Mdm2 and decrease p53 stability to suppress chemotherapy-induced cell death is another example.¹³² Lastly, NF-κB-mediated suppression of the p53-related p73 factor antagonizes apoptosis in antigen-stimulated naïve T cells.¹³³ This raises the possibility that a similar mechanism might operate in an oncogenic setting, although this remains to be established.

Cell Proliferation

Independent studies highlight a link between Rel/NF-κB's effects on cell proliferation and oncogenesis. Consistent with the critical role of the c-Rel subunit in B cell proliferation,¹³⁴^,¹³⁵ lymphoid cells transformed by a temperature-sensitive mutant of v-Rel fail to proliferate at the restrictive temperature under conditions where apoptosis is rescued by cell death inhibitor Bcl-2.¹²⁷ Aside from generating autocrine loops to constitutively activate the NF-κB pathway in tumor cells (see above), NF-κB activates expression of factors that influence cell cycle entry such as cyclins D1, D2 and D3 (Table 2).¹⁹^,¹³⁵^-¹³⁷ These findings concur with the elevated levels of cyclin D2 in malignant H/RS cells and cyclin D1 in mantle cell lymphoma and breast cancers that display sustained NF-κB activity, as well as in MMTV-c-rel-induced mouse mammary carcinoma.¹⁹^,⁹²^,¹³⁸

NF-κB can also enhance proliferation by activating other transcription factors. Some of them directly contribute to v-Rel-mediated transformation of lymphoid cells (Table 2). For example transcription factor AP-1(c-Jun) is essential for v-Rel's transforming activity in primary lymphoid cells and fibroblasts.¹³⁹ Both c-Jun and JunB are aberrantly expressed in malignant H/RS cells of HD, where upregulation of JunB is NF-κB-dependent.¹⁴⁰ These factors act together with NF-κB to stimulate H/RS cell proliferation and expression of cyclin D2, Bcl-xL, c-met and chemokine receptor CCR7. Other examples are interferon regulatory factor 4 (IRF 4) that decreases induction of the anti-proliferative IFN pathway and facilitates v-Rel-mediated transformation¹⁴¹ and c-Myc, a target of p50/c-Rel dimers that is induced in MMTV-c-rel mouse mammary tumors.⁹²^,¹⁴² Stat5a recently joined this group as an NF-κB target that is activated constitutively in HD and is linked to cell growth regulation.¹⁰

Angiogenesis and Metastasis

The ability of tumor cells to acquire sustained angiogenesis, invade surrounding tissues and metastasize to remote sites is one of the most significant factors contributing to cancer patient mortality. Here too NF-κB makes an important contribution by inducing expression of factors that promote angiogenesis (Table 2). Elevated NF-κB activity in cancer cells enables deregulated production of chemokines and chemokine receptors, like IL-8 and CXCR4, which increase migratory activity and promote angiogenesis.¹⁴³^,¹⁴⁴ NF-κB-mediated induction of vascular endothelial growth factor (VEGF) is another important contributing factor.¹⁴⁴^,¹⁴⁵ NF-κB also promotes invasion of surrounding tissues by inducing various cell adhesion molecules and matrix metalloproteinases.⁷^,¹⁴⁵ Together, these factors contribute to the pathogenesis of NF-κB in cancer.

Other Means for NF-κB to Participate in Oncogenesis

Several protein interactions and post-translational modifications modulate the transcriptional activity of NF-κB, and in some cases its contribution to oncogenesis.

Interaction with Transcription Factors and Coactivators

v-Rel and its cellular homologues c-Rel and RelA functionally interact with basal transcription factors and transcriptional coactivators to synergistically enhance gene transcription (for example see refs. 146-148). In some instances, interactions were confirmed in transformed lymphoid cells.¹⁴⁶ Although various coactivators like CBP/p300, TAFII105 or TAFII250 mediate NF-κB dependent transcription of anti-apoptotic genes, their implication in a tumor context is awaiting.¹⁴⁹^-¹⁵³ However PARP (Poly-ADP ribose polymerase-1) that behaves as a coactivator for NF-κB was recently implicated in NF-κB-mediated susceptibility to skin cancer induced by DMBA and TPA in mice but their coordinate action in human carcinogenesis remains to be verified.¹⁵⁴^,¹⁵⁵

Post-Translational Modifications

Phosphorylation, acetylation and ubiquitination of NF-κB subunits influence their activity, although in many cases evidence of their role in NF-κB-associated tumors has yet to be obtained.

Various kinases including IKK, casein kinase II and AKT enhance the transcriptional activities of p65/RelA and c-Rel by phosphorylating their TAD.¹⁵⁶^-¹⁶² Moreover, mutation of certain serines in the v-Rel TAD decreases its transcriptional activity and impairs transformation of lymphoid cells.¹⁰⁶ In addition, the catalytic subunit of PKA (PKAc), MSK1 and PKCη phosphorylate the RHD of p65/RelA and modification by PKAc is necessary for p65 interaction with coactivator p300.¹⁶³^-¹⁶⁶ Of interest, serine phosphorylation in the C-terminal domain of Bcl-3 by GSK3 affects its interaction with HDACs and is correlated with attenuation of its transforming potential in a mouse model.¹⁶⁷ Acetylation bestows another level of regulation, as exemplified by reversible p300/CBP- and P/CAF-mediated acetylation of p65/RelA that blocks association with IκBa and promotes p65 nuclear localization, DNA binding, and transactivation.¹⁶⁸^-¹⁷¹

A role for the ubiquitin-proteasome pathway in directly regulating the stability of NF-κB subunits came to light in work showing that C-terminally truncated c-Rel mutants and v-Rel display reduced proteasome-mediated turnover coincident with oncogenic transformation.¹⁷² Since then, poly-ubiquitination of p65/RelA was implicated in terminating the NF-κB response.¹⁷³ In this regard, the peptidyl-prolyl isomerase Pin1 was recently described to enhance NF-κB activity by associating with nuclear p65 to prevent its SOCS-1-mediated ubiquitination and degradation.¹⁷⁴ The fact that Pin1 is highly overexpressed in human breast cancer suggests a possible role for Pin1 in enhancing the oncogenic activity of NF-κB in certain tumors.

A Tumor Suppressor Role for NF-κB

Despite a large body of evidence supporting a positive role for Rel/NF-κB in oncogenesis, a growing number of studies indicate that NF-κB can behave as a tumor suppressor in some circumstances.¹⁷⁵^,¹⁷⁶ Indeed RelA opposes the action of TNFR1 and JNK to curb epidermal cell growth, and suppression of NF-κB in skin cooperates with oncogenic lesions such as oncogenic Ras to favor development of squamous cell carcinoma.¹⁷⁷^-¹⁸¹ Consistent with this, immortalized relA-/- fibroblasts induce tumors in SCID mice.¹⁸² Moreover, RelA actively represses transcription of anti-apoptotic genes in response to certain stimuli such as UV-C and chemotherapeutic agents doxorubicin or daunorubicin,¹⁸³ although others found NF-κB to be protective in this context.¹⁸⁴^,¹⁸⁵

The interaction of NF-κB with tumor suppressors to downregulate proproliferative or antiapoptotic genes, or to induce expression of pro-death factors further supports the notion that NF-κB can inhibit tumor growth in certain settings (Table 2). ARF, best known for its role in activating p53 via inhibition of Mdm2, inhibits p65/RelA-mediated transcription by inducing p65 association with histone deacetylase HDAC1.¹⁸⁶ This effect is promoter specific, as it leads to downregulation of anti-apoptotic NF-κB target Bcl-xL but not IκBa. Similarly, tumor suppressor p53 converts transcriptionally active Bcl-3/p52 complexes into transcriptionally inactive p52/HDAC1 complexes that inhibit cyclin D1 expression to induce cell cycle arrest.¹⁸⁷ The significance of these findings is highlighted by the observation that c-Rel, p52 and Bcl-3 are activated in human breast cancer.⁹^,⁹⁵ Interestingly, tumor suppressor BRCA1 physically interacts with p65/RelA to enhance NF-κB-mediated transcription of proapoptotic gene Fas, while ING4 controls brain tumor angiogenesis by negatively regulating RelA's transcriptional activity.¹⁸⁸^,¹⁸⁹ Lastly, NF-κB was reported to be required for p53-dependent apoptosis,¹⁹⁰ and recent work implicated the serine/threonine kinase ribosomal S6 kinase 1 (RSK1) in its p53-mediated activation.¹⁹¹ While one study found that NF-κB activation by doxorubicin decreases p53 stability,¹³² another showed that NF-κB stabilizes p53 to provoke apoptosis in response to genotoxic stress.¹⁹² Regardless of the mechanisms involved, the capacity of NF-κB to sometimes behave as a tumor suppressor has obvious implications for its role in oncogenesis and for therapeutic approaches aimed at inhibiting its activity (see below).

Conclusions and Perspectives for Therapy

While additional work is needed to pinpoint the precise role of Rel/NF-κB in human cancer and the mechanisms involved, a parallel has emerged between activities needed for lymphoid cell transformation and lymphomagenesis induced by the v-Rel and c-Rel proteins and those observed in many human tumors displaying constitutive NF-κB activity. These include inappropriate activation of cellular gene expression and aberrant expression of proproliferative and antiapoptotic genes. While the Rel proteins are potently oncogenic in avian species, the delayed onset of tumors in transgenic mice expressing v-rel or an MMTV-c-rel transgene suggests that additional cytogenetic alterations are necessary for NF-κB to manifest its oncogenic phenotype in mammals.⁸⁵^,⁹² Recent studies uncovered a crucial role for interaction between inflammatory cells and precancerous cells in tumor promotion and showed that NF-κB is critical in this process.¹⁹³^-¹⁹⁵ Thus, identification of the genes and pathways that act cooperatively with NF-κB in human cancer is an important goal in the field.

The NF-κB pathway constitutes an important therapeutic target.¹⁴⁵ NF-κB is implicated in the intrinsic resistance of cancer cells to apoptosis and the induced chemoresistance of many tumors to anti-cancer drugs, and its inhibition often enhances the effectiveness of treatment (for example see refs. 119, 121, 184). However recent advances uncovered a more complex scenario, by revealing that NF-κB can sometimes repress transcription of anti-apoptotic genes in response to “atypical” activators including several chemotherapeutic agents.¹⁷⁵^,¹⁸³ Its interaction with tumor suppressors such as p53, ARF and BRCA1 is another potentially important factor in the outcome of cancer therapy. Careful attention should thus be given to the tumor cell type, the death-inducing agent and perhaps other cytogenetic alterations in these tumors. Ongoing studies in the field promise to further advance our understanding of the transcriptional, anti-/pro-proliferative and anti/pro-apoptotic functions of NF-κB, the modifications and factors that modulate its activity and their impact on the oncogenic process. Together these will help to develop and improve appropriate strategies for cancer therapy tailored to particular contexts.

Acknowledgments

We are very grateful to N. Perkins for sharing a review article before publication. We apologize to many investigators whose work could not be cited due to space limitations. Research in this laboratory on the roles of Rel/NF-κB and its anti-apoptotic target Bfl-1/A1 in apoptosis and oncogenesis is supported by grants from the National Institutes of Health — National Cancer Institute CA54999 and CA83937 to CG. The first three authors contributed equally to this review.

References

1.: Rayet B, Gélinas C. Aberrant rel/nf-κB genes and activity in human cancer. Oncogene. 1999;18:6938–6947. [PubMed: 10602468]
2.: Gilmore TD, Kalaitzidis D, Liang MC. et al. The c-Rel transcription factor and B-cell proliferation: A deal with the devil. Oncogene. 2004;23:2275–2286. [PubMed: 14755244]
3.: Gilmore TD, Mosialos G. Viruses as intruders in the Rel/NF-kappaB signaling pathway. In: Beyaert R, ed. The Nuclear Factor κB: Regulation and Role in Defense. The Netherlands: Kluwer Academic Publishers. 2003:91–115.
4.: Kucharczak J, Simmons MJ, Fan Y. et al. To be, or not to be: NF-kappaB is the answer-role of Rel/NF-kappaB in the regulation of apoptosis. Oncogene. 2003;22:8961–8982. [PubMed: 14663476]
5.: Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nat Immunol. 2002;3:221–227. [PubMed: 11875461]
6.: Lin A, Karin M. NF-kappaB in cancer: A marked target. Semin Cancer Biol. 2003;13:107–114. [PubMed: 12654254]
7.: Baldwin AS. Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB. J Clin Invest. 2001;107:241–246. [PMC free article: PMC199203] [PubMed: 11160144]
8.: Sovak MA, Bellas RE, Kim DW. et al. Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer. J Clin Invest. 1997;100:2952–2960. [PMC free article: PMC508506] [PubMed: 9399940]
9.: Cogswell PC, Guttridge DC, Funkhouser WK. et al. Selective activation of NF-κB subunits in human breast cancer: Potential roles for NF-κB2/p52 and for Bcl-3. Oncogene. 2000;19:1123–1131. [PubMed: 10713699]
10.: Hinz M, Lemke P, Anagnostopoulos I. et al. Nuclear factor κB-dependent gene expression profiling of Hodgkin's disease tumor cells, pathogenic significance, and link to constitutive signal transducer and activator of transcription 5a activity. J Exp Med. 2002;196:605–617. [PMC free article: PMC2194004] [PubMed: 12208876]
11.: Alizadeh A, Eisen M, Davis R. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–511. [PubMed: 10676951]
12.: Davis RE, Brown KD, Siebenlist U. et al. Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J Exp Med. 2001;194:1861–1874. [PMC free article: PMC2193582] [PubMed: 11748286]
13.: Bargou R, Emmerich F, Krappmann D. et al. Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells. J Clin Invest. 1997;100:2961–2969. [PMC free article: PMC508507] [PubMed: 9399941]
14.: Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: The control of NF-kappaB activity. Annu Rev Immunol. 2000;18:621–663. [PubMed: 10837071]
15.: Sun S-C, Xiao G. Deregulation of NF-kappaB and its upstream kinases in cancer. Cancer Metastasis Rev. 2003;22:405–422. [PubMed: 12884915]
16.: Ravi R, Bedi A. NF-kappaB in cancer-a friend turned foe. Drug Resist Updat. 2004;7:53–67. [PubMed: 15072771]
17.: Lu T, Sathe SS, Swiatkowski SM. et al. Secretion of cytokines and growth factors as a general cause of constitutive NFkappaB activation in cancer. Oncogene. 2004;23:2138–2145. [PubMed: 14676835]
18.: Vale T, Ngo TT, White MA. et al. Raf-induced transformation requires an interleukin 1 autocrine loop. Cancer Res. 2001;61:602–607. [PubMed: 11212256]
19.: Hinz M, Loser P, Mathas S. et al. 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. 2001;97:2798–2807. [PubMed: 11313274]
20.: Brummelkamp TR, Nijman SM, Dirac AM. et al. Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB. Nature. 2003;424:797–801. [PubMed: 12917690]
21.: Kovalenko A, Chable-Bessia C, Cantarella G. et al. The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature. 2003;424:801–805. [PubMed: 12917691]
22.: Trompouki E, Hatzivassiliou E, Tsichritzis T. et al. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature. 2003;424:793–796. [PubMed: 12917689]
23.: Wilkinson KD. Signal transduction: Aspirin, ubiquitin and cancer. Nature. 2003;424:738–739. [PubMed: 12917671]
24.: Hu MC, Lee DF, Xia W. et al. IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004;117:225–237. [PubMed: 15084260]
25.: Yamamoto Y, Verma UN, Prajapati S. et al. Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression. Nature. 2003;423:655–659. [PubMed: 12789342]
26.: Anest V, Hanson JL, Cogswell PC. et al. A nucleosomal function for IkappaB kinase-alpha in NF-kappaB-dependent gene expression. Nature. 2003;423:659–663. [PubMed: 12789343]
27.: Verma UN, Yamamoto Y, Prajapati S. et al. Nuclear role of I kappa B Kinase-gamma/NF-kappa B essential modulator (IKK gamma/NEMO) in NF-kappa B-dependent gene expression. J Biol Chem. 2004;279:3509–3515. [PubMed: 14597638]
28.: Pianetti S, Arsura M, Romieu-Mourez R. et al. Her-2/neu overexpression induces NF-κB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IκBa that can be inhibited by the tumor supressor PTEN. Oncogene. 2001;20:1287–1299. [PubMed: 11313873]
29.: Romieu-Mourez R, Landesman-Bollag E, Seldin DC. et al. Protein kinase CK2 promotes aberrant activation of nuclear factor-kappaB, transformed phenotype, and survival of breast cancer cells. Cancer Res. 2002;62:6770–6778. [PubMed: 12438279]
30.: Cavin LG, Romieu-Mourez R, Panta GR. et al. Inhibition of CK2 activity by TGF-beta1 promotes IkappaB-alpha protein stabilization and apoptosis of immortalized hepatocytes. Hepatology. 2003;38:1540–1551. [PubMed: 14647065]
31.: Reuther JY, Reuther GW, Cortez G. et al. A requirement for NF-κB activation in Bcr-Abl-mediated transformation. Genes Dev. 1998;12:968–981. [PMC free article: PMC316671] [PubMed: 9531535]
32.: Nawata R, Yujiri T, Nakamura Y. et al. MEK kinase 1 mediates the antiapoptotic effect of the Bcr-Abl oncogene through NF-kappaB activation. Oncogene. 2003;22:7774–7780. [PubMed: 14586403]
33.: Korus M, Mahon GM, Cheng L. et al. p38 MAPK-mediated activation of NF-kappaB by the RhoGEF domain of Bcr. Oncogene. 2002;21:4601–4612. [PubMed: 12096337]
34.: Finco TS, Westwick JK, Norris JL. et al. Oncogenic Ha-Ras-induced signaling activates NF-kappaB transcriptional activity, which is required for cellular transformation. J Biol Chem. 1997;272:24113–24116. [PubMed: 9305854]
35.: Mayo MW, Wang CY, Cogswell PC. et al. Requirement of NF-kappa B activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science. 1997;278:1812–1815. [PubMed: 9388187]
36.: Jeay S, Pianetti S, Kagan HM. et al. Lysyl oxidase inhibits ras-mediated transformation by preventing activation of NF-kappa B. Mol Cell Biol. 2003;23:2251–2263. [PMC free article: PMC150722] [PubMed: 12640111]
37.: Stoffel A, Chaurushiya M, Singh B. et al. Activation of NF-kappaB and inhibition of p53-mediated apoptosis by API2/mucosa-associated lymphoid tissue 1 fusions promote oncogenesis. Proc Natl Acad Sci USA. 2004;101:9079–9084. [PMC free article: PMC428476] [PubMed: 15184680]
38.: Yamaoka S, Inoue H, Sakurai M. et al. Constitutive activation of NF-kappa B is essential for transformation of rat fibroblasts by the human T-cell leukemia virus type I Tax protein. EMBO J. 1996;15:873–887. [PMC free article: PMC450285] [PubMed: 8631308]
39.: Rousset R, Desbois C, Bantignies F. et al. Effects on NF-κB1/p105 processing of the interaction between the HTLV-1 transactivator Tax and the proteasome. Nature. 1996;381:328–331. [PubMed: 8692272]
40.: Li XH, Gaynor RB. Mechanisms of NF-kappaB activation by the HTLV type 1 tax protein. AIDS Res Hum Retroviruses. 2000;16:1583–1590. [PubMed: 11080795]
41.: Mosialos G. The role of Rel/NF-kappa B proteins in viral oncogenesis and the regulation of viral transcription. Seminars in Cancer Biology. 1997;8:121–129. [PubMed: 9299590]
42.: Xiao G, Cvijic ME, Fong A. et al. Retroviral oncoprotein tax induces processing of NF-kappaB2/ p100 in T cells: Evidence for the involvement of IKKalpha. EMBO J. 2001;20:6805–6815. [PMC free article: PMC125766] [PubMed: 11726516]
43.: Cahir-McFarland ED, Davidson DM, Schauer SL. et al. NF-kappa B inhibition causes spontaneous apoptosis in Epstein-Barr virus-transformed lymphoblastoid cells. Proc Natl Acad Sci USA. 2000;97:6055–6060. [PMC free article: PMC18557] [PubMed: 10811897]
44.: Cahir-McFarland E, Kieff E. NF-kappaB inhibition in EBV-transformed lymphoblastoid cell lines. Recent Results Cancer Res. 2002;159:44–48. [PubMed: 11785843]
45.: D'Souza BN, Edelstein LC, Pegman PM. et al. Nuclear factor kappa B-dependent activation of the antiapoptotic bfl-1 gene by the Epstein-Barr virus latent membrane protein 1 and activated CD40 receptor. J Virol. 2004;78:1800–1816. [PMC free article: PMC369510] [PubMed: 14747545]
46.: Eliopoulos AG, Caamano JH, Flavell J. et al. Epstein-Barr virus-encoded latent infection membrane protein 1 regulates the processing of p100 NF-kappaB2 to p52 via an IKKgamma/NEMO-independent signalling pathway. Oncogene. 2003;22:7557–7569. [PubMed: 14576817]
47.: Perkins ND. Oncogenes, tumor suppressors and p52 NF-kappaB. Oncogene. 2003;22:7553–7556. [PubMed: 14576816]
48.: Cabannes E, Khan G, Aillet F. et al. Mutations in the IκBa gene in Hodgkin's disease suggest a tumour suppressor role for IkappaBalpha. Oncogene. 1999;18:3063–3070. [PubMed: 10340377]
49.: Krappmann D, Emmerich F, Kordes U. et al. Molecular mechanisms of constitutive NF-kappaB/Rel activation in Hodgkin/Reed-Sternberg cells. Oncogene. 1999;18:943–953. [PubMed: 10023670]
50.: Wood KM, Roff M, Hay RT. Defective IkappaBalpha in Hodgkin cell lines with constitutively active NF-kappaB. Oncogene. 1998;16:2131–2139. [PubMed: 9572494]
51.: Jungnickel B, Staratschek-Jox A, Brauninger A. et al. Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin's lymphoma. J Exp Med. 2000;191:395–402. [PMC free article: PMC2195754] [PubMed: 10637284]
52.: Emmerich F, Theurich S, Hummel M. et al. Inactivating IκBε mutations in Hodgkin/ Reed-Sternberg cells. J Pathol. 2003;201:413–420. [PubMed: 14595753]
53.: Kalaitzidis D, Davis RE, Rosenwald A. et al. The human B-cell lymphoma cell line RC-K8 has multiple genetic alterations that dysregulate the Rel/NF-κB signal transduction pathway. Oncogene. 2002;21:8759–8768. [PubMed: 12483529]
54.: Chang C-C, Zhang J, Lombardi L. et al. Mechanism of expression and role in transcriptional control of the proto-oncogene NFκB-2/LYT-10. Oncogene. 1994;9:923–933. [PubMed: 8108136]
55.: Fracchiolla NS, Lombardi L, Salina M. et al. Structural alterations of the NF-kappa B transcription factor lyt-10 in lymphoid malignancies. Oncogene. 1993;8:2839–2845. [PubMed: 8378093]
56.: Migliazza A, Lombardi L, Rocchi M. et al. Heterogeneous chromosomal aberrations generate 3' truncations of the NFκB2/lyt-10 gene in lymphoid malignancies. Blood. 1994;84:3850–3860. [PubMed: 7949142]
57.: Neri A, Fracchiolla NS, Roscetti E. et al. Molecular analysis of cutaneous B- and T-cell lymphomas. Blood. 1995;86:3160–3172. [PubMed: 7579411]
58.: Thakur S, Lin HC, Tseng WT. et al. Rearrangement and altered expression of the NFκB2 gene in human cutaneous T-lymphoma cells. Oncogene. 1994;9:2335–2344. [PubMed: 8036016]
59.: Wang Y, Cui H, Schroering A. et al. NF-kappa B2 p100 is a pro-apoptotic protein with anti-oncogenic function. Nat Cell Biol. 2002;4:888–893. [PubMed: 12389034]
60.: Hacker H, Karin M. Is NF-kappaB2/p100 a direct activator of programmed cell death? Cancer Cell. 2002;2:431–433. [PubMed: 12498710]
61.: Caamano JH, Rizzo CA, Durham SK. et al. Nuclear factor (NF)-kappa B2 (p100/p52) is required for normal splenic microarchitecture and B cell-mediated immune responses. J Exp Med. 1998;187:185–196. [PMC free article: PMC2212102] [PubMed: 9432976]
62.: Franzoso G, Carlson L, Poljak L. et al. Mice deficient in nuclear factor (NF)-kappa B/p52 present with defects in humoral responses, germinal center reactions, and splenic microarchitecture. J Exp Med. 1998;187:147–159. [PMC free article: PMC2212099] [PubMed: 9432973]
63.: Ishikawa H, Carrasco D, Claudio E. et al. Gastric hyperplasia and increased proliferative responses of lymphocytes in mice lacking the COOH-terminal ankyrin domain of NF-kappaB2. J Exp Med. 1997;186:999–1014. [PMC free article: PMC2199059] [PubMed: 9314550]
64.: Xiao G, Harhaj E, Sun SC. NF-κB-inducing kinase regulates the processing of NF-κB2 p100. Mol Cell. 2001;7:401–409. [PubMed: 11239468]
65.: Dejardin E, Bonizzi G, Bellahcene A. et al. Highly expressed p100/p52 (NFκB2) sequesters other NFκB-related proteins in the cytoplasm of human breast cancer cells. Oncogene. 1995;11:1835–1841. [PubMed: 7478612]
66.: Bours V, Dejardin E, Goujon-Letawe F. et al. The NF-κB transcription factor and cancer: High expression of NF-κB- and IκB-related proteins in tumor cell lines. Biochem Pharmacol. 1994;47:145–149. [PubMed: 8311838]
67.: Viatour P, Bentires-Alj M, Chariot A. et al. NF- kappa B2/p100 induces Bcl-2 expression. Leukemia. 2003;17:1349–1356. [PubMed: 12835724]
68.: Barth TF, Martin-Subero JI, Joos S. et al. Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin lymphoma. Blood. 2003;101:3681–3686. [PubMed: 12511414]
69.: Savage KJ, Monti S, Kutok JL. et al. 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. 2003;102:3871–3879. [PubMed: 12933571]
70.: Houldsworth J, Olshen AB, Cattoretti G. et al. Relationship between REL amplification, REL function, and clinical and biologic features in diffuse large B-cell lymphomas. Blood. 2004;103:1862–1868. [PubMed: 14615382]
71.: Rosenwald A, Staudt LM. Gene expression profiling of diffuse large B-cell lymphoma. Leuk Lymphoma. 2003;44(Suppl 3):S41–47. [PubMed: 15202524]
72.: Gilmore TD, Starczynowski DT, Kalaitzidis D. et al. RELevant gene amplification in B-cell lymphomas? Blood. 2004;103:3243–3245. [PubMed: 15070712]
73.: Theilen G, Zeigel R, Tweihaus M. Biological studies with RE virus (strain T) that induces reticuloendotheliosis in turkeys, chickens, and Japanese quails. J Natl Cancer Inst. 1966;37:747–749. [PubMed: 4289067]
74.: Gilmore TD. Multiple mutations contribute to the oncogenicity of the retroviral oncoprotein v-Rel. Oncogene. 1999;18:6925–6937. [PubMed: 10602467]
75.: Rice NR, Copeland TD, Simek S. et al. Detection and characterization of the protein encoded by the v-rel oncogene. Virology. 1986;149:217–229. [PubMed: 3004027]
76.: Zhang JY, Olson W, Ewert D. et al. The v-rel oncogene of avian reticuloendotheliosis virus transforms immature and mature lymphoid cells of the B cell lineage in vitro. Virology. 1991;183:457–466. [PubMed: 1677223]
77.: Barth CF, Ewert DL, Olson WC. et al. Reticuloendotheliosis virus REV-T(REV-A)-induced neoplasia: Development of tumors within the T-lymphoid and myeloid lineages. J Virol. 1990;64:6054–6062. [PMC free article: PMC248779] [PubMed: 1700831]
78.: Boehmelt G, Madruga J, Dorfler P. et al. Dendritic cell progenitor is transformed by a conditional v-rel estrogen receptor fusion protein v-relER. Cell. 1995;80:341–352. [PubMed: 7834754]
79.: Beug H, Muller H, Doederlein G. et al. Hematopoietic cells transformed in vitro by REV-T avian reticuloendotheliosis virus express characteristics of very immature lymphoid cells. Virology. 1981;115:295–309. [PubMed: 6274086]
80.: Moore BE, Bose HR. Expression of the v-rel oncogene in reticuloendotheliosis virus-transformed fibroblasts. Virology. 1988;162:377–387. [PubMed: 2829425]
81.: Gélinas C, Temin HM. The v-rel oncogene encodes a cell-specific transcriptional activator of certain promoters. Oncogene. 1988;3:349–355. [PubMed: 2856247]
82.: Hannink M, Temin HM. Transactivation of gene expression by nuclear and cytoplasmic rel proteins. Mol Cell Biol. 1989;9:4323–4336. [PMC free article: PMC362513] [PubMed: 2555689]
83.: Schwartz RC, Witte ON. A recombinant murine retrovirus expressing v-rel is cytopathic. Virology. 1988;165:182–190. [PubMed: 2838956]
84.: Gilmore TD, Jean-Jacques J, Richards R. et al. Stable expression of the avian retroviral oncoprotein v-Rel in avian, mouse, and dog cell lines. Virology. 2003;316:9–16. [PubMed: 14599786]
85.: Carrasco D, Rizzo CA, Dorfman K. et al. The v-rel oncogene promotes malignant T-cell leukemia/lymphoma in transgenic mice. EMBO J. 1996;15:3640–3650. [PMC free article: PMC451988] [PubMed: 8670867]
86.: Kim SH, Mitchell M, Fujii H. et al. Absence of p16INK4a and truncation of ARF tumor suppressors in chickens. Proc Natl Acad Sci USA. 2003;100:211–216. [PMC free article: PMC140929] [PubMed: 12506196]
87.: Fan Y, Rayet B, Gélinas C. Divergent C-terminal transactivation domains of Rel/NF-κB proteins are critical determinants of their oncogenic potential in lymphocytes. Oncogene. 2004;23:1030–1042. [PubMed: 14647412]
88.: Hrdlickova R, Nehyba J, Humphries EH. v-rel induces expression of three avian immunoregulatory surface receptors more efficiently than c-rel. J Virol. 1994;68:308–319. [PMC free article: PMC236290] [PubMed: 8254742]
89.: Nehyba J, Hrdlickova R, Humphries EH. Evolution of the oncogenic potential of v-rel: Rel-induced expression of immunoregulatory receptors correlates with tumor development and in vitro transformation. J Virol. 1994;68:2039–2050. [PMC free article: PMC236677] [PubMed: 8138989]
90.: Kralova J, Schatzle JD, Bargmann W. et al. Transformation of avian fibroblasts overexpressing the c-rel proto-oncogene and a variant of c-rel lacking 40 C-terminal amino acids. J Virol. 1994;68:2073–2083. [PMC free article: PMC236681] [PubMed: 8138992]
91.: Gilmore TD, Cormier C, Jean-Jacques J. et al. Malignant transformation of primary chicken spleen cells by human transcription factor c-Rel. Oncogene. 2001;20:7098–7103. [PubMed: 11704834]
92.: Romieu-Mourez R, Kim DW, Shin SM. et al. Mouse mammary tumor virus c-rel transgenic mice develop mammary tumors. Mol Cell Biol. 2003;23:5738–5754. [PMC free article: PMC166341] [PubMed: 12897145]
93.: Nakshatri H, Bhat-Nakshatri P, Martin DA. et al. Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol. 1997;17:3629–3639. [PMC free article: PMC232215] [PubMed: 9199297]
94.: Kim DW, Sovak MA, Zanieski G. et al. Activation of NF-kappaB/Rel occurs early during neoplastic transformation of mammary cells. Carcinogenesis. 2000;21:871–879. [PubMed: 10783306]
95.: Romieu-Mourez R, Landesman-Bollag E, Seldin DC. et al. Roles of IKK kinases and protein kinase CK2 in activation of nuclear factor-kappaB in breast cancer. Cancer Res. 2001;61:3810–3818. [PubMed: 11325857]
96.: Hrdlickova R, Nehyba J, Humphries EH. In vivo evolution of c-rel oncogenic potential. J Virol. 1994;68:2371–2382. [PMC free article: PMC236714] [PubMed: 8139023]
97.: Romero P, Humphries EH. A mutant v-rel with increased ability to transform B lymphocytes. J Virol. 1995;69:301–307. [PMC free article: PMC188576] [PubMed: 7983722]
98.: Kumar S, Rabson AB, Gélinas C. The RxxRxRxxC motif conserved in all Rel/κB proteins is essential for the DNA-binding activity and redox regulation of the v-Rel oncoprotein. Mol Cell Biol. 1992;12:3094–3106. [PMC free article: PMC364524] [PubMed: 1620118]
99.: Morrison LE, Boehmelt G, Enrietto PJ. Mutations in the rel-homology domain alter the biochemical properties of v-rel and render it transformation defective in chicken fibroblasts. Oncogene. 1992;7:1137–1147. [PubMed: 1594245]
100.: White DW, Gilmore TD. Temperature-sensitive transforming mutants of the v-rel oncogene. J Virol. 1993;67:6876–6881. [PMC free article: PMC238136] [PubMed: 8411392]
101.: Walker WH, Stein B, Ganchi PA. et al. The v-rel oncogene: Insights into the mechanism of transcriptional activation, repression and transformation. J Virol. 1992;66:5018–5029. [PMC free article: PMC241358] [PubMed: 1321284]
102.: Kamens J, Richardson P, Mosialos G. et al. Oncogenic transformation by vRel requires an amino-terminal activation domain. Mol Cell Biol. 1990;10:2840–2847. [PMC free article: PMC360645] [PubMed: 2111443]
103.: Sarkar S, Gilmore TD. Transformation by the v-Rel oncoprotein requires sequences carboxy-terminal to the Rel homology domain. Oncogene. 1993;8:2245–2252. [PubMed: 8336947]
104.: Chen C, Agnés F, Gélinas C. Mapping of a serine-rich domain essential for the transcriptional, antiapoptotic, and transforming activities of the v-Rel oncoprotein. Mol Cell Biol. 1999;19:307–316. [PMC free article: PMC83888] [PubMed: 9858554]
105.: Chen C, Agnés F, Gélinas C. Mapping of a serine-rich domain essential for the transcriptional, antiapoptotic, and transforming activities of the v-Rel oncoprotein- Author's Correction. Mol Cell Biol. 2001;21:7115. [PMC free article: PMC83888] [PubMed: 9858554]
106.: Rayet B, Fan Y, Gélinas C. Mutations in the v-Rel transactivation domain indicate altered phosphorylation and identify a subset of NF-κB-regulated cell death inhibitors important for v-Rel transforming activity. Mol Cell Biol. 2003;23:1520–1533. [PMC free article: PMC151695] [PubMed: 12588973]
107.: Sachdev S, Diehl JA, McKinsey TA. et al. A threshold nuclear level of the v-Rel oncoprotein is required for transformation of avian lymphocytes. Oncogene. 1997;14:2585–2594. [PubMed: 9191058]
108.: Sachdev S, Hannink M. Loss of IκBa-mediated control over nuclear import and DNA binding enables oncogenic activation of c-Rel. Mol Cell Biol. 1998;18:5445–5456. [PMC free article: PMC109129] [PubMed: 9710628]
109.: Phelps CB, Ghosh G. Discreet mutations from c-Rel to v-Rel alter kappaB DNA recognition, IkappaBalpha binding, and dimerization: implications for v-Rel oncogenicity. Oncogene. 2004;23:1229–1238. [PubMed: 14961076]
110.: Malek S, Chen Y, Huxford T. et al. IkappaBbeta, but not IkappaBalpha, functions as a classical cytoplasmic inhibitor of NF-kappaB dimers by masking both NF-kappaB nuclear localization sequences in resting cells. J Biol Chem. 2001;276:45225–45235. [PubMed: 11571291]
111.: Tam WF, Wang W, Sen R. Cell-specific association and shuttling of IkappaBalpha provides a mechanism for nuclear NF-kappaB in B lymphocytes. Mol Cell Biol. 2001;21:4837–4846. [PMC free article: PMC87179] [PubMed: 11416157]
112.: Carrasco D, Perez P, Lewin A. et al. IκBa overexpression delays tumor formation in v-rel transgenic mice. J Exp Med. 1997;186:279–288. [PMC free article: PMC2198979] [PubMed: 9221757]
113.: Nehyba J, Hrdlickova R, Bose Jr HR. Differences in kappaB DNA-binding properties of v-Rel and c-Rel are the result of oncogenic mutations in three distinct functional regions of the Rel protein. Oncogene. 1997;14:2881–2897. [PubMed: 9205096]
114.: Liss AS, Bose Jr HR. Mutational analysis of the v-Rel dimerization interface reveals a critical role for v-Rel homodimers in transformation. J Virol. 2002;76:4928–4939. [PMC free article: PMC136140] [PubMed: 11967310]
115.: Starczynowski DT, Reynolds JG, Gilmore TD. Deletion of either C-terminal transactivation subdomain enhances the in vitro transforming activity of human transcription factor REL in chicken spleen cells. Oncogene. 2003;22:6928–6936. [PubMed: 14534540]
116.: Karin M, Cao Y, Greten FR. et al. NF-kappaB in cancer: From innocent bystander to major culprit. Nat Rev Cancer. 2002;2:301–310. [PubMed: 12001991]
117.: Wang CY, Guttridge DC, Mayo MW. et al. NF-kappaB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. Mol Cell Biol. 1999;19:5923–5929. [PMC free article: PMC84448] [PubMed: 10454539]
118.: Mathas S, Lietz A, Anagnostopoulos I. et al. c-FLIP mediates resistance of Hodgkin/Reed-Sternberg cells to death receptor-induced apoptosis. J Exp Med. 2004;199:1041–1052. [PMC free article: PMC2211891] [PubMed: 15078899]
119.: Wang CY, Cusack Jr JC, Liu R. et al. Control of inducible chemoresistance: Enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-kappaB. Nat Med. 1999;5:412–417. [PubMed: 10202930]
120.: Cusack Jr JC, Liu R, Baldwin Jr AS. Inducible chemoresistance to 7-ethyl-10-[4-(1-piperidino)- 1-piperidino]-carbonyloxycamptothe cin (CPT-11) in colorectal cancer cells and a xenograft model is overcome by inhibition of nuclear factor-kappaB activation. Cancer Res. 2000;60:2323–2330. [PubMed: 10811101]
121.: Baldwin Jr AS. Series introduction: the transcription factor NF-kappaB and human disease. J Clin Invest. 2001;107:3–6. [PMC free article: PMC198555] [PubMed: 11134170]
122.: White DW, Roy A, Gilmore TD. The v-Rel oncoprotein blocks apoptosis and proteolysis of IκBa in transformed chicken spleen cells. Oncogene. 1995;10:857–868. [PubMed: 7898928]
123.: Zong WX, Farrell M, Bash J. et al. v-Rel prevents apoptosis in transformed lymphoid cells and blocks TNFalpha-induced cell death. Oncogene. 1997;15:971–980. [PubMed: 9285692]
124.: Lee RM, Gillet G, Burnside J. et al. Role of Nr13 in regulation of programmed cell death in the bursa of Fabricius. Genes Dev. 1999;13:718–728. [PMC free article: PMC316554] [PubMed: 10090728]
125.: You M, Bose Jr HR. Identification of v-Rel oncogene-induced inhibitor of apoptosis by differential display. Methods. 1998;16:373–385. [PubMed: 10049645]
126.: Kralova J, Liss AS, Bargmann W. et al. Differential regulation of the inhibitor of apoptosis ch-IAP1 by v-rel and the proto-oncogene c-rel. J Virol. 2002;76:11960–11970. [PMC free article: PMC136878] [PubMed: 12414938]
127.: White DW, Gilmore TD. Bcl-2 and CrmA have different effects on transformation, apoptosis and the stability of IκBa in chicken spleen cells transformed by temperature-sensitive v-Rel oncoproteins. Oncogene. 1996;13:891–899. [PubMed: 8806678]
128.: Perkins ND, Felzien LK, Betts JC. et al. Regulation of NF-kappaB by cyclin-dependent kinases associated with the p300 coactivator. Science. 1997;275:523–527. [PubMed: 8999795]
129.: Wadgaonkar R, Phelps KM, Haque Z. et al. CREB-binding protein is a nuclear integrator of nuclear factor-kappaB and p53 signaling. J Biol Chem. 1999;274:1879–1882. [PubMed: 9890939]
130.: Webster G, Perkins N. Transcriptional cross talk between NF-kappaB and p53. Mol Cell Biol. 1999;19:3485–3495. [PMC free article: PMC84141] [PubMed: 10207072]
131.: Vasudevan KM, Gurumurthy S, Rangnekar VM. Suppression of PTEN expression by NF-kappa B prevents apoptosis. Mol Cell Biol. 2004;24:1007–1021. [PMC free article: PMC321419] [PubMed: 14729949]
132.: Tergaonkar V, Pando M, Vafa O. et al. p53 stabilization is decreased upon NFkappaB activation: A role for NFkappaB in acquisition of resistance to chemotherapy. Cancer Cell. 2002;1:493–503. [PubMed: 12124178]
133.: Wan YY, DeGregori J. The survival of antigen-stimulated T cells requires NFkappaB-mediated inhibition of p73 expression. Immunity. 2003;18:331–342. [PubMed: 12648451]
134.: Grumont RJ, Rourke IJ, O'Reilly LA. et al. B lymphocytes differentially use the Rel and nuclear factor κB1 (NF-κB1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. J Exp Med. 1998;187:663–674. [PMC free article: PMC2212175] [PubMed: 9480976]
135.: Hsia CY, Cheng S, Owyang AM. et al. c-Rel regulation of the cell cycle in primary mouse B lymphocytes. Int Immunol. 2002;14:905–916. [PubMed: 12147627]
136.: Guttridge DC, Albanese C, Reuther JY. et al. NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol. 1999;19:5785–5799. [PMC free article: PMC84428] [PubMed: 10409765]
137.: Hinz M, Krappmann D, Eichten A. et al. NF-κB function in growth control: Regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol Cell Biol. 1999;19:2690–2698. [PMC free article: PMC84062] [PubMed: 10082535]
138.: Pham LV, Tamayo AT, Yoshimura LC. et al. Inhibition of constitutive NF-kappa B activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol. 2003;171:88–95. [PubMed: 12816986]
139.: Kralova J, Liss AS, Bargmann W. et al. AP-1 factors play an important role in transformation induced by the v-rel oncogene. Mol Cell Biol. 1998;18:2997–3009. [PMC free article: PMC110679] [PubMed: 9566919]
140.: Mathas S, Hinz M, Anagnostopoulos I. et al. Aberrantly expressed c-Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF-kappa B. EMBO J. 2002;21:4104–4113. [PMC free article: PMC126136] [PubMed: 12145210]
141.: Hrdlickova R, Nehyba J, Bose Jr HR. Interferon regulatory factor 4 contributes to transformation of v-Rel-expressing fibroblasts. Mol Cell Biol. 2001;21:6369–6386. [PMC free article: PMC99785] [PubMed: 11533227]
142.: Lee H, Arsura M, Wu M. et al. Role of Rel-related factors in control of c-myc gene transcription in receptor-mediated apoptosis of the murine B cell WEHI 231 line. J Exp Med. 1995;181:1169–1177. [PMC free article: PMC2191927] [PubMed: 7869034]
143.: Helbig G, Christopherson IInd KW, Bhat-Nakshatri P. et al. NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem. 2003;278:21631–21638. [PubMed: 12690099]
144.: Huang S, Robinson JB, Deguzman A. et al. Blockade of nuclear factor-kappaB signaling inhibits angiogenesis and tumorigenicity of human ovarian cancer cells by suppressing expression of vascular endothelial growth factor and interleukin 8. Cancer Res. 2000;60:5334–5339. [PubMed: 11034066]
145.: Garg A, Aggarwal BB. Nuclear transcription factor-kappaB as a target for cancer drug development. Leukemia. 2002;16:1053–1068. [PubMed: 12040437]
146.: Xu X, Prorock C, Ishikawa H. et al. Functional interaction of the v-Rel and c-Rel oncoproteins with the TATA-binding protein and association with transcription factor IIB. Mol Cell Biol. 1993;13:6733–6741. [PMC free article: PMC364736] [PubMed: 8413269]
147.: Schmitz ML, Stelzer G, Altmann H. et al. Interaction of the COOH-terminal transactivation domain of p65 NF-kappa B with TATA-binding protein, transcription factor IIB, and coactivators. J Biol Chem. 1995;270:7219–7226. [PubMed: 7706261]
148.: Kerr LD, Ransone LJ, Wamsley P. et al. Association between proto-oncoprotein Rel and TATA-binding protein mediates transcriptional activation by NF-kappa B. Nature. 1993;365:412–419. [PubMed: 8413585]
149.: Yamit-Hezi A, Dikstein R. TAFII105 mediates activation of anti-apoptotic genes by NF-κB. EMBO J. 1998;17:5161–5169. [PMC free article: PMC1170844] [PubMed: 9724652]
150.: Yamit-Hezi A, Nir S, Wolstein O. et al. Interaction of TAFII105 with selected p65/RelA dimers is associated with activation of subset of NF-kappa B genes. J Biol Chem. 2000;275:18180–18187. [PubMed: 10849440]
151.: Edelstein LC, Lagos L, Simmons M. et al. NF-kappa B-dependent assembly of an enhanceosome-like complex on the promoter region of apoptosis inhibitor Bfl-1/A1. Mol Cell Biol. 2003;23:2749–2761. [PMC free article: PMC152543] [PubMed: 12665576]
152.: Sheppard KA, Rose DW, Haque ZK. et al. Transcriptional activation by NF-kappaB requires multiple coactivators. Mol Cell Biol. 1999;19:6367–6378. [PMC free article: PMC84607] [PubMed: 10454583]
153.: Guermah M, Malik S, Roeder RG. Involvement of TFIID and USA components in transcriptional activation of the human immunodeficiency virus promoter by NF-kappaB and Sp1. Mol Cell Biol. 1998;18:3234–3244. [PMC free article: PMC108905] [PubMed: 9584164]
154.: Hassa PO, Buerki C, Lombardi C. et al. Transcriptional coactivation of nuclear factor-kappaB-dependent gene expression by p300 is regulated by poly(ADP)-ribose polymerase-1. J Biol Chem. 2003;278:45145–45153. [PubMed: 12960163]
155.: Martin-Oliva D, O'Valle F, Munoz-Gamez JA. et al. Crosstalk between PARP-1 and NF-kappaB modulates the promotion of skin neoplasia. Oncogene. 2004;23:5275–5283. [PubMed: 15077172]
156.: Wang D, Baldwin Jr AS. Activation of NF-κB-dependent transcription by tumor necrosis factor-alpha is mediated through phosphorylation of RelA/p65 on serine 529. J Biol Chem. 1998;273:29411–29416. [PubMed: 9792644]
157.: Sakurai H, Chiba H, Miyoshi H. et al. IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine 536 in the transactivation domain. J Biol Chem. 1999;274:30353–30356. [PubMed: 10521409]
158.: Martin AG, Fresno M. Tumor necrosis factor-alpha activation of NF-kappa B requires the phosphorylation of Ser-471 in the transactivation domain of c-Rel. J Biol Chem. 2000;275:24383–24391. [PubMed: 10823840]
159.: Wang D, Westerheide SD, Hanson JL. et al. Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II. J Biol Chem. 2000;275:32592–32597. [PubMed: 10938077]
160.: Mayo MW, Madrid LV, Westerheide SD. et al. PTEN blocks tumor necrosis factor-induced NF-kappa B-dependent transcription by inhibiting the transactivation potential of the p65 subunit. J Biol Chem. 2002;277:11116–11125. [PubMed: 11799112]
161.: Sizemore N, Lerner N, Dombrowski N. et al. Distinct roles of the Ikappa B kinase alpha and beta subunits in liberating nuclear factor kappa B (NF-kappa B) from Ikappa B and in phosphorylating the p65 subunit of NF-kappa B. J Biol Chem. 2002;277:3863–3869. [PubMed: 11733537]
162.: Yang F, Tang E, Guan K. et al. IKKbeta plays an essential role in the phosphorylation of RelA/p65 on serine 536 induced by lipopolysaccharide. J Immunol. 2003;170:5630–5635. [PubMed: 12759443]
163.: Zhong H, Voll RE, Ghosh S. Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Mol Cell. 1998;1:661–671. [PubMed: 9660950]
164.: Zhong H, SuYang H, Erdjument-Bromage H. et al. The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism. Cell. 1997;89:413–424. [PubMed: 9150141]
165.: Duran A, Diaz-Meco MT, Moscat J. Essential role of RelA Ser311 phosphorylation by zetaPKC in NF-kappaB transcriptional activation. EMBO J. 2003;22:3910–3918. [PMC free article: PMC169043] [PubMed: 12881425]
166.: Vermeulen L, De Wilde G, Van Damme P. et al. Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J. 2003;22:1313–1324. [PMC free article: PMC151081] [PubMed: 12628924]
167.: Viatour P, Dejardin E, Warnier M. et al. GSK3-mediated BCL-3 phosphorylation modulates its degradation and its oncogenicity. Mol Cell. 2004;16:35–45. [PubMed: 15469820]
168.: Ashburner BP, Westerheide SD, Baldwin Jr AS. The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression. Mol Cell Biol. 2001;21:7065–7077. [PMC free article: PMC99882] [PubMed: 11564889]
169.: Chen LF, Mu Y, Greene WC. Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB. EMBO J. 2002;21:6539–6548. [PMC free article: PMC136963] [PubMed: 12456660]
170.: Chen LF, Greene WC. Regulation of distinct biological activities of the NF-kappaB transcription factor complex by acetylation. J Mol Med. 2003;81:549–557. [PubMed: 12920522]
171.: Kiernan R, Bres V, Ng RW. et al. Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65. J Biol Chem. 2003;278:2758–2766. [PubMed: 12419806]
172.: Chen E, Hrdlickova R, Nehyba J. et al. Degradation of proto-oncoprotein c-Rel by the ubiquitin-proteasome pathway. J Biol Chem. 1998;273:35201–35207. [PubMed: 9857058]
173.: Saccani S, Marazzi I, Beg AA. et al. Degradation of promoter-bound p65/RelA is essential for the prompt termination of the nuclear factor kappaB response. J Exp Med. 2004;200:107–113. [PMC free article: PMC2213320] [PubMed: 15226358]
174.: Ryo A, Suizu F, Yoshida Y. et al. Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol Cell. 2003;12:1413–1426. [PubMed: 14690596]
175.: Campbell KJ, Perkins ND. Reprogramming RelA. Cell Cycle. 2004;3:869–872. [PubMed: 15190199]
176.: Perkins ND. NF-kappaB: Tumor promoter or suppressor? Trends Cell Biol. 2004;14:64–69. [PubMed: 15102437]
177.: Zhang JY, Green CL, Tao S. et al. NF-kappaB RelA opposes epidermal proliferation driven by TNFR1 and JNK. Genes Dev. 2004;18:17–22. [PMC free article: PMC314269] [PubMed: 14724177]
178.: Lind MH, Rozell B, Wallin RP. et al. Tumor necrosis factor receptor 1-mediated signaling is required for skin cancer development induced by NF-kappaB inhibition. Proc Natl Acad Sci USA. 2004;101:4972–4977. [PMC free article: PMC387358] [PubMed: 15044707]
179.: Dajee M, Lazarov M, Zhang JY. et al. NF-κB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature. 2003;421:639–643. [PubMed: 12571598]
180.: van Hogerlinden M, Rozell BL, Ahrlund-Richter L. et al. Squamous cell carcinomas and increased apoptosis in skin with inhibited Rel/nuclear factor-kappaB signaling. Cancer Res. 1999;59:3299–3303. [PubMed: 10416581]
181.: van Hogerlinden M, Auer G, Toftgard R. Inhibition of Rel/Nuclear Factor-kappaB signaling in skin results in defective DNA damage-induced cell cycle arrest and Ha-ras- and p53-independent tumor development. Oncogene. 2002;21:4969–4977. [PubMed: 12118375]
182.: Gapuzan ME, Yufit PV, Gilmore TD. Immortalized embryonic mouse fibroblasts lacking the RelA subunit of transcription factor NF-κB have a malignantly transformed phenotype. Oncogene. 2002;21:2484–2492. [PubMed: 11971183]
183.: Campbell KJ, Rocha S, Perkins ND. Active repression of antiapoptotic gene expression by RelA(p65) NF-kappa B. Mol Cell. 2004;13:853–865. [PubMed: 15053878]
184.: Wang CY, Mayo MW, Baldwin Jr AS. TNF- and cancer therapy-induced apoptosis: Potentiation by inhibition of NF-kappaB. Science. 1996;274:784–787. [PubMed: 8864119]
185.: Tergaonkar V, Bottero V, Ikawa M. et al. IkappaB kinase-independent IkappaBalpha degradation pathway: Functional NF-kappaB activity and implications for cancer therapy. Mol Cell Biol. 2003;23:8070–8083. [PMC free article: PMC262380] [PubMed: 14585967]
186.: Rocha S, Campbell KJ, Perkins ND. p53- and Mdm2-independent repression of NF-kappa B transactivation by the ARF tumor suppressor. Mol Cell. 2003;12:15–25. [PubMed: 12887889]
187.: Rocha S, Martin AM, Meek DW. et al. p53 represses cyclin D1 transcription through down regulation of Bcl-3 and inducing increased association of the p52 NF-kappaB subunit with histone deacetylase 1. Mol Cell Biol. 2003;23:4713–4727. [PMC free article: PMC164841] [PubMed: 12808109]
188.: Benezra M, Chevallier N, Morrison D. et al. BRCA1 augments transcription by the NF-kappaB transcription factor by binding to the Rel domain of the p65/RelA subunit. J Biol Chem. 2003;278:26333–26341. [PubMed: 12700228]
189.: Garkavtsev I, Kozin SV, Chernova O. et al. The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis. Nature. 2004;428:328–332. [PubMed: 15029197]
190.: Ryan KM, Ernst MK, Rice NR. et al. Role of NF-κB in p53-mediated programmed cell death. Nature. 2000;404:892–897. [PubMed: 10786798]
191.: Bohuslav J, Chen LF, Kwon H. et al. p53 induces NF-kappaB activation by an IkappaB kinase-independent mechanism involving phosphorylation of p65 by ribosomal S6 kinase 1. J Biol Chem. 2004;279:26115–26125. [PubMed: 15073170]
192.: Fujioka S, Schmidt C, Sclabas GM. et al. Stabilization of p53 is a novel mechanism for proapoptotic function of NF-kappaB. J Biol Chem. 2004;279:27549–27559. [PubMed: 15102862]
193.: Greten FR, Eckmann L, Greten TF. et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004;118:285–296. [PubMed: 15294155]
194.: Pikarsky E, Porat RM, Stein I. et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431:461–466. [PubMed: 15329734]
195.: Balkwill F, Coussens LM. An inflammatory link. Nature. 2004;431:405–406. [PubMed: 15385993]

Bookshelf ID: NBK6169

Contents

< Prev Next >

PubReader
Print View
Cite this Page
Fan Y, Dutta J, Gupta N, et al. Molecular Basis of Oncogenesis by NF-κB: From a Bird's Eye View to a RELevant Role in Cancer. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

In this Page

Introduction
Constitutive Rel/NF-κB Activity Is a Hallmark of Many Human Cancers
Molecular Basis for Oncogenesis by Rel/NF-κB
Functional Consequences of Rel/NF-κB-Mediated Gene Activation in Oncogenesis
Other Means for NF-κB to Participate in Oncogenesis
Conclusions and Perspectives for Therapy
Acknowledgments
References

Related information

PMC
PubMed Central citations
PubMed
Links to PubMed

Recent Activity

Clear Turn Off Turn On

Molecular Basis of Oncogenesis by NF-κB: From a Bird's Eye View to a RELevant Ro...
Molecular Basis of Oncogenesis by NF-κB: From a Bird's Eye View to a RELevant Role in Cancer - Madame Curie Bioscience Database
Hepatocyte Transplantation and Liver-Directed Gene Therapy - Madame Curie Biosci...
Hepatocyte Transplantation and Liver-Directed Gene Therapy - Madame Curie Bioscience Database
Laminopathies: One Gene, Two Proteins, Five Diseases.. - Madame Curie Bioscience...
Laminopathies: One Gene, Two Proteins, Five Diseases.. - Madame Curie Bioscience Database
Structural and Functional Relation of Neuropilins - Madame Curie Bioscience Data...
Structural and Functional Relation of Neuropilins - Madame Curie Bioscience Database
Fibroblast Growth Factors - Madame Curie Bioscience Database
Fibroblast Growth Factors - Madame Curie Bioscience Database

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Bookshelf

Madame Curie Bioscience Database [Internet].

Molecular Basis of Oncogenesis by NF-κB: From a Bird's Eye View to a RELevant Role in Cancer

Authors

Affiliations

Introduction

Constitutive Rel/NF-κB Activity Is a Hallmark of Many Human Cancers

Activation of the NF-κB Signaling Cascade

Table 1

IKK Complex Activation

Table 2

Activation by Other Kinases, Oncogenes and Viruses

iκB Gene Mutations

nf-κB Gene Rearrangement, Amplification and/or Overexpression in Human Cancer

Molecular Basis for Oncogenesis by Rel/NF-κB

The Viral NF-κB Oncoprotein v-Rel: A Potent Transforming Factor

A Role for c-Rel in Cell Transformation and Tumorigenesis: Lessons from Birds and Mice

Rel/NF-κB Functions Necessary for Cell Transformation

Functional Consequences of Rel/NF-κB-Mediated Gene Activation in Oncogenesis

Suppression of Apoptosis

Cell Proliferation

Angiogenesis and Metastasis

Other Means for NF-κB to Participate in Oncogenesis

Interaction with Transcription Factors and Coactivators

Post-Translational Modifications

A Tumor Suppressor Role for NF-κB

Conclusions and Perspectives for Therapy

Acknowledgments

References

Views

In this Page

Related information

Recent Activity