The lack of transcriptional activation of the v-erbA oncogene is in part due to a mutation present in the DNA binding domain of the protein.
Using a transient co-transfection system we have demonstrated that response elements for estrogen (ER), thyroid hormone (TR) and retinoic acid receptors (RAR) are closely related. Thyroid hormone-induced activation of transcription was observed in CV1 cells and not in HeLa cells, suggesting the existence of cell-specific transcription factors necessary for the response. By contrast to its cellular counterpart (c-erbA/cTR alpha) the oncogene protein gag v-erbA is unable to activate gene transcription from different response elements derived from the rat growth hormone (rGH) gene promoter. A chimeric construct consisting of the ER in which the DNA binding domain has been replaced by that of cTR alpha was able to stimulate the reporter gene. In contrast, a construct in which ER DNA binding domain has been replaced by that of gag v-erbA did not activate gene transcription. These results lead us to the conclusion that the mutated DNA binding domain of v-erbA is in part responsible for the lack of transcriptional activation and in repression of gene expression. This is due in large part to the Gly73----Ser mutation which corresponds to the position of one of the three discriminating amino acids that are thought to interact with a specific base of the response element.
de Verneuil
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Laboratoire de Génétique Moléculaire des Eucaryotes du CNRS, Unité 184 de Biologie Moléculaire, Faculté de Médecine, Strasbourg, France.
Metzger
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D000595:Amino Acid Sequence; D001483:Base Sequence; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D018774:Oncogene Proteins v-erbA; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000235:genetics; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics* / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D002352:Carrier Proteins; D018774:Oncogene Proteins v-erbA; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D015682:Retroviridae Proteins, Oncogenic; D014157:Transcription Factors; D013006:Growth Hormone; D004247:DNA