Mapping of a serine-rich domain essential for the transcriptional, antiapoptotic, and transforming activities of the v-Rel oncoprotein.
The v-Rel oncoprotein belongs to the Rel/NF-kappaB family of transcription factors and induces aggressive lymphomas in chickens and transgenic mice. Current models for cell transformation by v-Rel invoke the combined activation of gene expression and the dominant inhibition of transcription mediated by its cellular homologs. Here, we mapped a serine-rich transactivation domain in the C terminus of v-Rel that is necessary for its biological activity. Specific serine-to-alanine substitutions within this region impaired the transcriptional activity of v-Rel, whereas a double mutant abolished its function. In contrast, substitutions with phosphomimetic aspartate residues led to a complete recovery of the transcriptional potential. The transforming activity of v-Rel mutants correlated with their ability to inhibit programmed cell death. The transforming and antiapoptotic activities of v-Rel were abolished by defined Ser-to-Ala mutations and restored by most Ser-to-Asp substitutions. However, one Ser-to-Asp mutant showed wild-type transactivation ability but failed to block apoptosis and to transform cells. These results show that the transactivation function of v-Rel is necessary but not sufficient for cell transformation, adding an important dimension to the transformation model. It is possible that defined protein-protein interactions are also required to block apoptosis and transform cells. Since v-Rel is an acutely oncogenic member of the Rel/NF-kappaB family, our data raise the possibility that phosphorylation of its serine-rich transactivation domain may regulate its unique biological activity.
Chen
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Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5638, USA.
Agnès
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F
Gélinas
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D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001224:Aspartic Acid; D001665:Binding Sites; D019556:COS Cells; D002471:Cell Transformation, Neoplastic; D002645:Chickens; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D020572:Oncogene Proteins v-rel; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020569:Proto-Oncogene Proteins c-rel; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics* / Q000378:metabolism; D012694:Serine; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D020572:Oncogene Proteins v-rel; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D015682:Retroviridae Proteins, Oncogenic; D001224:Aspartic Acid; D012694:Serine