V-erbA requires auxiliary proteins for dominant negative activity.
The avian v-erbA protein is an important example of a dominant negative oncogene. It has been identified as a highly mutated form of its cellular homolog, the thyroid hormone receptor alpha (TR-alpha), and its biological activity has been correlated with its repressor function on certain receptor-regulated genes. Although v-erbA has lost the hormone responsiveness of its cellular homolog, it has retained DNA-binding activity, and it has been implied that this function is required for repression and transformation. Here we demonstrate that v-erbA forms heterodimers with the retinoid X receptor (RXR-alpha). Only heteromeric v-erbA-RXR-alpha complexes show DNA-binding strong enough to account for its potent repressor function. In addition, v-erbA-RXR-alpha heterodimers specifically bind natural thyroid hormone-responsive elements (TREs) but not retinoic acid-responsive elements (RAREs). Repression of TRE-controlled gene expression by v-erbA requires the presence of RXR-alpha with the natural TREs tested. In contrast, natural RAREs investigated here do not bind the v-erbA-RXR-alpha heterodimer and also are not significantly repressed by v-erbA. Carboxy-terminal mutations that abolish v-erbA-RXR-alpha heterodimer formation also abolish v-erbA repressor activity. These data suggest that interaction of v-erbA with RXRs or similar auxiliary receptors is essential for the dominant negative activity of the v-erbA oncogene.
Hermann
T
T
Cancer Research Centre, La Jolla Cancer Research Foundation, California 92037.
Hoffmann
B
B
Piedrafita
F J
FJ
Zhang
X K
XK
Pfahl
M
M
D001483:Base Sequence; D002352:Carrier Proteins / Q000502:physiology; D004247:DNA / Q000378:metabolism; D005799:Genes, Dominant; D008969:Molecular Sequence Data; D018774:Oncogene Proteins v-erbA; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors; D011956:Receptors, Cell Surface / Q000502:physiology*; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone / Q000502:physiology; D012097:Repressor Proteins / Q000494:pharmacology; D047488:Retinoid X Receptors; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors
D002352:Carrier Proteins; D018774:Oncogene Proteins v-erbA; D016755:Proto-Oncogene Proteins c-jun; D011956:Receptors, Cell Surface; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D015682:Retroviridae Proteins, Oncogenic; D014157:Transcription Factors; D004247:DNA