Divergent C-terminal transactivation domains of Rel/NF-kappa B proteins are critical determinants of their oncogenic potential in lymphocytes.
rel/nf-kappaB 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-kappaB 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 IKKbeta 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-kappaB1, p52/NF-kappaB2, 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-kappaB factors in leukemia/lymphomagenesis in an in vivo animal model, and are consistent with the implication of c-rel in many human lymphomas.
Fan
Yongjun
Y
Center for Advanced Biotechnology and Medicine, Piscataway, NJ 08854-5638, USA.
Rayet
Béatrice
B
Gélinas
Céline
C
D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002472:Cell Transformation, Viral; D002645:Chickens; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D020569:Proto-Oncogene Proteins c-rel / Q000737:chemistry / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D013154:Spleen / Q000166:cytology; D018243:Teratocarcinoma; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D016328:NF-kappa B; D020569:Proto-Oncogene Proteins c-rel; D015534:Trans-Activators