Identification of a domain required for oncogenic activity and transcriptional suppression by v-erbA and thyroid-hormone receptor alpha.
v-erbA, a mutated version of the chicken thyroid hormone (TH) receptor type alpha, can inhibit hormonal induction of target genes. In addition, v-erbA acts as a constitutive repressor of the basal promoter activity. In vivo, v-erbA can arrest the differentiation of erythroid precursor cells and suppresses transcription of erythrocyte-specific genes. We show that the v-erbA protein of the transformation-defective avian erythroblastosis virus mutant (AEVtd359) fails to suppress basal transcription level and exhibits impaired ability in antagonizing the TH and retinoic acid response. The inactivating mutation is a 1-nt change leading to a Pro-->Arg replacement in the "hinge region" of v-erbA protein. Introducing this mutation in the context of TH receptor alpha selectively inactivates the suppressor function, while hormone-binding and transcriptional-activation properties are unaffected. These data suggest that trans-repression rather than a dominant negative block of TH-receptor or retinoic acid-receptor activation may represent the primary molecular property underlying erbA oncogenesis.
Damm
K
K
Department of Neuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
Evans
R M
RM
D001355:Alpharetrovirus / Q000235:genetics; D000595:Amino Acid Sequence; D002472:Cell Transformation, Viral / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D015967:Gene Expression Regulation, Viral; D008969:Molecular Sequence Data; D018774:Oncogene Proteins v-erbA; D017433:Protein Structure, Secondary; D018168:Receptors, Retinoic Acid / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000737:chemistry / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015682:Retroviridae Proteins, Oncogenic / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D014162:Transfection
D004268:DNA-Binding Proteins; D018774:Oncogene Proteins v-erbA; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D015682:Retroviridae Proteins, Oncogenic