Characterization of changes in gene expression associated with malignant transformation by the NF-κB family member, v-Rel

Petrenko, Oleksi; Ischenko, Irene; Enrietto, Paula J.

doi:10.1038/sj.onc.1201334

Cited by 17 publications

(14 citation statements)

References 34 publications

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“…Although this alone could not fully explain their different transforming efficiencies, we found that cc-Rel-A1, -A2, -A3 and sw-vTAD differentially activated kB site-dependent gene expression in infected cells (Figure 2h). For example, activation of mip-1b, that transformation-defective v-Rel mutants fail to induce (Petrenko et al, 1997), was more closely correlated with their increased transforming activity than activation of irf-4 (Figure 2h; Hrdlickova´et al, 2001). Thus, despite decreasing c-Rel's intrinsic transactivation potency on luciferase reporters, TAD1 and TAD2 mutations can promote gene-specific activation and markedly improve its transforming potential.…”

mentioning

confidence: 93%

An optimal range of transcription potency is necessary for efficient cell transformation by c-Rel to ensure optimal nuclear localization and gene-specific activation

Fan

Gélinas

2006

Oncogene

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c-Rel is overexpressed in several B-cell lymphomas and c-rel gene overexpression can transform primary chicken lymphoid cells and induce tumors in animals. Although c-Rel is generally a stronger transcriptional activator than its viral derivative v-Rel, its oncogenic activity is significantly weaker. Among the mutations acquired during c-Rel's evolution into v-Rel are deletion of c-Rel's transactivation domain 2 (cTAD2) and mutations in cTAD1. Given the critical role of the Rel TADs in cell transformation, we investigated how mutations in c-Rel's cTAD1 and cTAD2 contribute to its oncogenicity and that of v-Rel. Mutations in cTAD2 noticeably increased c-Rel's transforming activity by promoting its nuclear localization and gene-specific transactivation, despite an overall decrease in jB site-dependent transactivation potency. Conversely, substitution of vTAD by cTAD1 increased v-Rel's transactivation and transforming efficiencies, whereas its substitution by the stronger cTAD2 compromised activation of mip-1b but not irf-4 and was detrimental to cell transformation. These results suggest that the Rel TADs differentially contribute to genespecific activation and that an optimal range of transcription potency is necessary for efficient transformation. These findings may have important implications for understanding how Rel TAD mutations can lead to a more oncogenic phenotype.

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mentioning

confidence: 93%

An optimal range of transcription potency is necessary for efficient cell transformation by c-Rel to ensure optimal nuclear localization and gene-specific activation

Fan

Gélinas

2006

Oncogene

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“…This ®nding supports the conclusion that c-RelER is a conditional version of c-Rel. We previously reported that three of these genes, Sca-2, MIP-1b, and IkB-a, are also up-regulated in v-Reltransformed ®broblasts and hematopoietic cells (Petrenko et al, 1997). Interestingly, most genes identi®ed so far as v-Rel targets are also upregulated in cells transformed by c-Rel.…”

Section: Discussionmentioning

confidence: 97%

“…Three genes were initially examined, those encoding the cytoplasmic inhibitor IkB-a, a cell surface antigen Sca-2, and a chicken homologue of the mammalian macrophage in¯ammatory protein-1 beta (Mip-1b). Previous studies established that these genes are constitutively activated in c-Rel-transformed fibroblasts and v-Rel-transformed hematopoietic cells (Kralova et al, 1994;Petrenko et al, 1997). This study allowed us to correlate the transformationspeci®c alterations of c-RelER ®broblasts with the transcriptional activity of the chimeric protein.…”

Section: E Ect Of C-reler On Expression Of Cellular Genesmentioning

confidence: 87%

“…However, the kinetics and relative levels of their expression di er in each case. Thus, v-Rel induces higher levels of MHC class I and II, IL-2R, DM-GRASP and p75 in lymphoid cells (HrdlicÏ kovaÂ et al, 1995Zhang et al, 1995;Zhang and Humphries, 1996), while c-Rel induces higher levels of NF-kB1, IkB-a, and c-myb in lymphoid cells and ®broblasts (HrdlicÏ kovaÂ et al, 1995;Petrenko et al, 1997). Consistent with these results, v-Rel and Dc-Rel appear to be stronger activators of IkB-a and Mip1b expression in the transformed ®broblasts, while cRel induced higher levels of Sca-2 and 9E3/CEF4.…”

Section: Discussionmentioning

confidence: 99%

“…Hybridization probes were prepared by random priming of gel-puri®ed c-DNA inserts. The cDNAs encoding chicken MIP-1b and Sca-2 were isolated in this laboratory (Petrenko et al, 1995, Petrenko et al, 1997.…”

Section: Rna Isolation and Northern Analysismentioning

confidence: 99%

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A chicken c-Rel-estrogen receptor chimeric protein shows conditional nuclear localization, DNA binding, transformation and transcriptional activation

et al. 1998

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In this report, we characterize the biological and biochemical properties of a conditional protein containing chicken c-Rel fused to the hormone-binding domain of the human estrogen receptor. This chimeric c-RelER protein causes estrogen-dependent, but otherwise c-Relspeci®c, transformation of avian ®broblasts in vitro. Our results demonstrate that c-RelER heterodimerizes with wild-type c-Rel and forms speci®c complexes with IkB-a. Estrogen causes translocation of c-RelER to the nucleus and stabilizes its binding to DNA. Hormone-activated cRelER induces transcription of at least four cellular genes that are constitutively active in wild-type c-Reltransformed ®broblasts. Two distinct cell populations were examined that di ered with respect to their growth phenotypes. The growth of ®broblasts with moderate expression levels of c-RelER was stimulated by estrogen. In contrast, the addition of estrogen to cells with high cRelER expression levels resulted in inhibition of cytokinesis and the arrest of growth. The carboxy terminal transactivation domain of c-Rel was required for the induction of these e ects since neither v-Rel nor c-Rel deletion mutants were able to induce similar changes. Taken together, our results demonstrate that high levels of c-Rel expression can a ect cell cycle control and/or cytokinesis. Furthermore, they also indicate that the biological properties of c-Rel in cell growth and di erentiation will potentially di er depending on the level of expression.

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Stimulation of c-Rel transcriptional activity by PKA catalytic subunit ?

Yu¹,

Chiang²,

Shih

et al. 2004

J Mol Med

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Nuclear factor kappaB (NF-kappaB) is a eukaryotic transcription factor which responds to different extracellular signals. It is involved in immune response, inflammation, and cell proliferation. Increased expression of c-Rel (or its viral homolog v-Rel), one component of the NF-kappaB factors, induces tumorigenesis in different systems. The activity of NF-kappaB can be regulated by protein kinase A (PKA) in a cAMP-independent manner. Our previous results showed that c-MYC induces the activity of PKA by inducing the transcription of the gene encoding the PKA catalytic subunit beta (PKA-Cbeta). Constitutive expression of PKA-Cbeta in Rat1a cells induces their transformation. Here we show that CREB is unlikely to be a phosphorylation target of PKA-Cbeta as characterized by different cell lines. Electrophoretic mobility shift assays showed that c-Rel is present as a significant component of the NF-kappaB factors in c-MYC overexpressing status. The transcriptional activity of c-Rel was significantly stimulated by PKA-Cbeta. Coactivators p300/CBP are at least partially responsible for the enhanced activation mediated by c-Rel and PKA-Cbeta. Interaction between c-Rel and PKA-Cbeta was demonstrated using coimmunoprecipitation assays. Immunoprecipitation-in vitro phosphorylation assays showed the direct phosphorylation of c-Rel by PKA-Cbeta. These results indicate that c-Rel is a reasonable phosphorylation target of PKA-Cbeta, and that the transcriptional activity of c-Rel is stimulated by PKA-Cbeta possibly through the interaction with p300/CBP.

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Characterization of changes in gene expression associated with malignant transformation by the NF-κB family member, v-Rel

Cited by 17 publications

References 34 publications

An optimal range of transcription potency is necessary for efficient cell transformation by c-Rel to ensure optimal nuclear localization and gene-specific activation

An optimal range of transcription potency is necessary for efficient cell transformation by c-Rel to ensure optimal nuclear localization and gene-specific activation

A chicken c-Rel-estrogen receptor chimeric protein shows conditional nuclear localization, DNA binding, transformation and transcriptional activation

Stimulation of c-Rel transcriptional activity by PKA catalytic subunit ?

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