Identification of v-Rel Oncogene-Induced Inhibitor of Apoptosis by Differential Display

You, M. James; Bose, Henry R.

doi:10.1006/meth.1998.0692

Cited by 6 publications

(6 citation statements)

References 28 publications

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“…Cell death inhibitor bcl-xl complements the oncogenic defect of partially transforming v-Rel mutants. v-Rel was previously shown to display antiapoptotic activity, and this function was closely correlated with its oncogenic potential (3,8,45,74,78,79,83). In light of these observations, we asked whether the partially transforming phenotype of Ser-to-Ala v-Rel mutants A6.7 and A6.7.10 was caused, at least in part, by diminished antiapoptotic activity.…”

Section: The Transforming Activity Of V-rel Mutants Is Correlated Witmentioning

confidence: 98%

“…The cell cycle progression factor cyclin D1 was reported to be regulated by NF-B and is probably involved in cell transformation involving Bcl-3 proteins (27,72). The induction of death-inhibitory genes by v-Rel is likely to be an important and early event in the transformation process, as primary chicken lymphoid cells rapidly undergo apoptosis in culture unless a death-inhibitory program is activated by v-Rel (8,45,74,78,79,83). v-Rel therefore provides a valuable tool to address the role of NF-B in oncogenesis and the cellular genes involved in the physiologically relevant context of primary lymphoid cells.…”

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confidence: 99%

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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

Rayet

Fan

Gélinas

2003

Molecular and Cellular Biology

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Consistent with the constitutive activation of Rel/NF-B in human hematopoietic tumors, the v-Rel oncoprotein induces aggressive leukemia/lymphomas in animal models. v-Rel is thus a valuable tool to characterize the role of Rel/NF-B in cancer and the mechanisms involved. Prior studies by our group identified a serine-rich domain in v-Rel that was required for biological activity. Here, we investigated the molecular basis for the transformation defect of specific serine mutants. We show that the transforming efficiency of these mutants in primary lymphoid cells is correlated with their ability to mediate B site-dependent transactivation and with specific changes in phosphorylation profiles. Interestingly, coexpression of the death antagonists Bcl-xL and Bcl-2 significantly increased their oncogenicity, whereas other NF-B-regulated death inhibitors showed little or no effect. The fact that a subset of apoptosis inhibitors could rescue v-Rel transactivation mutants suggests that their reduced transcriptional activity may critically affect expression of defined death antagonists essential for oncogenesis. Consistent with this hypothesis, we observed selection for high endogenous expression of Bcl-2-related death antagonists in cells transformed by weakly transforming v-Rel mutants. These results emphasize the need for Rel/NF-B to efficiently activate expression of a subset of antiapoptotic genes from the Bcl-2 family to manifest its oncogenic phenotype.The Rel/NF-B family of transcription factors plays a key role in regulating immune and inflammatory responses and also participates in the control of cell proliferation and apoptosis, two functions that are critical in cancer. The implication of Rel/NF-B factors in malignancy was initially suggested by the acute oncogenicity of their viral derivative, the v-Rel oncoprotein. v-Rel induces aggressive and fatal lymphomas in chickens and transgenic mice. This phenotype can be accurately reproduced in vitro through malignant transformation of primary splenic lymphoid cells. Consistent with the oncogenic phenotype of v-Rel, cellular rel and nf-b genes are amplified, rearranged, overexpressed, and/or constitutively activated in human lymphoma, leukemia, myeloma, and Hodgkin's disease (reviewed in reference 49). Aberrant rel/nf-b genes and/or activity are also observed in solid tumors, including lung, breast, and colon carcinomas. Moreover, rel/nf-b genes serve as essential mediators for transformation by oncogenes such as bcr-abl, and RET (20,37,41,50). These observations highlight the importance of elucidating how Rel/NF-B functions in oncogenesis.

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Section: The Transforming Activity Of V-rel Mutants Is Correlated Witmentioning

confidence: 98%

mentioning

confidence: 99%

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

Rayet

Fan

Gélinas

2003

Molecular and Cellular Biology

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“…Cloning of sh3bgrl and site-directed mutagenesis Differential display and cloning of a full-length sh3bgrl cDNA were performed using techniques previously described (You and Bose, 1998). Briefly, 10 mg of total RNA was purified using the RNeasy kit (QIAGEN, Valencia, CA, USA) from normal CEFs, CEFs transfected with empty Rous sarcoma virusderived vector (RCAS), or CEFs transformed by RCASexpressing v-Rel.…”

Section: General Cell Culture Techniquesmentioning

confidence: 99%

The suppression of SH3BGRL is important for v-Rel-mediated transformation

et al. 2005

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The v-rel oncogene is the most efficient transforming member of the Rel/NF-jB family of transcription factors. v-Rel induces avian and mammalian lymphoid cell tumors and transforms chicken embryo fibroblasts in culture by the aberrant regulation of genes under the control of Rel/ NF-jB proteins. Here we report that the expression of SH3BGRL, a member of the SH3BGR (SH3 domainbinding glutamic acid-rich) family of proteins, is downregulated in v-Rel-expressing fibroblasts, lymphoid cells, and splenic tumor cells. Chromatin immunoprecipitation experiments demonstrated that v-Rel binds to the sh3bgrl promoter in transformed cells. Coexpression of SH3BGRL with v-Rel in primary splenic lymphocytes reduced the number of colonies formed by 76%. Mutations in the predicted SH3-binding domain of SH3BGRL abolished the suppressive effect on v-Rel transformation and resulted in colony numbers comparable to those formed by v-Rel alone. However, mutations in the predicted EVH1-binding domain of SH3BGRL only had a modest effect on suppression of v-Rel transformation. This study provides the first example of a gene that is downregulated in v-Rel-expressing cells that also plays a role in v-Rel transformation.

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“…Cloning and mutagenesis of TC10 Differential display was performed using total RNA from vRel transformed and control cells as described previously (You et al, 1997;You and Bose, 1998). A repertoire of cDNA fragments was amplified from each cell type using an RNAimage kit (GenHunter Corp., Nashville, TN, USA) with the H-T 11 G primer and a random primer set (H-AP1 to H-AP8).…”

Section: Methodsmentioning

confidence: 99%

“…Transformation by v-Rel is mediated by the inappropriate activation or suppression of genes, which are normally regulated by Rel/NF-kB proteins. Efforts to identify genes induced by v-Rel have led to the identification of more than two dozen genes (You and Bose, 1998;Gilmore, 1999;Hrdlickova´et al, 1999Hrdlickova´et al, , 2001Nehyba et al, 2002). However, only a few of these genes have been shown to contribute to the transformed phenotype.…”

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confidence: 99%

The activation of TC10, a Rho small GTPase, contributes to v-Rel-mediated transformation

et al. 2006

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Identification of v-Rel Oncogene-Induced Inhibitor of Apoptosis by Differential Display

Cited by 6 publications

References 28 publications

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

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

The suppression of SH3BGRL is important for v-Rel-mediated transformation

The activation of TC10, a Rho small GTPase, contributes to v-Rel-mediated transformation

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