Divergent C-terminal transactivation domains of Rei/NF-κB proteins are critical determinants of their oncogenic potential in lymphocytes

Yongjun Fan, Béatrice Rayet, Celine Gelinas

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

rel/nf-κB genes are amplified, overexpressed, or constitutively activated in many human hematopoietic tumors; however, the molecular mechanisms by which they contribute to tumorigenesis remain to be determined. Here, we explored the oncogenic potential of cellular Rel/ NF-κB proteins in vitro and in vivo. We show that overexpression of wild-type mouse and human c-rel genes suffices to malignantly transform primary spleen cells in stringent soft agar assays and produce fatal tumors in vivo. In contrast relA and a constitutively active form of IKKβ did not. Importantly, a hybrid RelA protein with its C-terminal transactivation domain substituted by that of v-Rel was potently oncogenic in vitro and in vivo. The transactivation domain of v-Rel selectively conferred an oncogenic phenotype upon the Rel homology domain (RHD) of RelA, but not to the more divergent RHDs of p50/NF-κB1, p52/NF-κB2, or RelB. Collectively, our results highlight important differences in the intrinsic oncogenic activity of mammalian c-Rel and RelA proteins, and indicate that critical determinants of their differential oncogenicity reside in their divergent transactivation domains. These findings provide experimental evidence for a role of mammalian Rel/NF-κB factors in leukemia/ lymphomagenesis in an in vivo animal model, and are consistent with the implication of c-rel in many human lymphomas.

Original languageEnglish (US)
Pages (from-to)1030-1042
Number of pages13
JournalOncogene
Volume23
Issue number5
DOIs
StatePublished - Feb 5 2004

Fingerprint

Transcriptional Activation
Lymphocytes
Proto-Oncogene Proteins c-rel
rel Genes
Agar
Lymphoma
Neoplasms
Carcinogenesis
Leukemia
Spleen
Animal Models
Phenotype
Genes
IgA receptor
Proteins
In Vitro Techniques
3'-(1-butylphosphoryl)adenosine

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Keywords

  • Cancer
  • NF-κB
  • Rel
  • Transcription
  • Transformation

Cite this

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abstract = "rel/nf-κB genes are amplified, overexpressed, or constitutively activated in many human hematopoietic tumors; however, the molecular mechanisms by which they contribute to tumorigenesis remain to be determined. Here, we explored the oncogenic potential of cellular Rel/ NF-κB proteins in vitro and in vivo. We show that overexpression of wild-type mouse and human c-rel genes suffices to malignantly transform primary spleen cells in stringent soft agar assays and produce fatal tumors in vivo. In contrast relA and a constitutively active form of IKKβ did not. Importantly, a hybrid RelA protein with its C-terminal transactivation domain substituted by that of v-Rel was potently oncogenic in vitro and in vivo. The transactivation domain of v-Rel selectively conferred an oncogenic phenotype upon the Rel homology domain (RHD) of RelA, but not to the more divergent RHDs of p50/NF-κB1, p52/NF-κB2, or RelB. Collectively, our results highlight important differences in the intrinsic oncogenic activity of mammalian c-Rel and RelA proteins, and indicate that critical determinants of their differential oncogenicity reside in their divergent transactivation domains. These findings provide experimental evidence for a role of mammalian Rel/NF-κB factors in leukemia/ lymphomagenesis in an in vivo animal model, and are consistent with the implication of c-rel in many human lymphomas.",
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Divergent C-terminal transactivation domains of Rei/NF-κB proteins are critical determinants of their oncogenic potential in lymphocytes. / Fan, Yongjun; Rayet, Béatrice; Gelinas, Celine.

In: Oncogene, Vol. 23, No. 5, 05.02.2004, p. 1030-1042.

Research output: Contribution to journalArticle

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AB - rel/nf-κB genes are amplified, overexpressed, or constitutively activated in many human hematopoietic tumors; however, the molecular mechanisms by which they contribute to tumorigenesis remain to be determined. Here, we explored the oncogenic potential of cellular Rel/ NF-κB proteins in vitro and in vivo. We show that overexpression of wild-type mouse and human c-rel genes suffices to malignantly transform primary spleen cells in stringent soft agar assays and produce fatal tumors in vivo. In contrast relA and a constitutively active form of IKKβ did not. Importantly, a hybrid RelA protein with its C-terminal transactivation domain substituted by that of v-Rel was potently oncogenic in vitro and in vivo. The transactivation domain of v-Rel selectively conferred an oncogenic phenotype upon the Rel homology domain (RHD) of RelA, but not to the more divergent RHDs of p50/NF-κB1, p52/NF-κB2, or RelB. Collectively, our results highlight important differences in the intrinsic oncogenic activity of mammalian c-Rel and RelA proteins, and indicate that critical determinants of their differential oncogenicity reside in their divergent transactivation domains. These findings provide experimental evidence for a role of mammalian Rel/NF-κB factors in leukemia/ lymphomagenesis in an in vivo animal model, and are consistent with the implication of c-rel in many human lymphomas.

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