The erbA oncogene represses the actions of both retinoid X and retinoid A receptors but does so by distinct mechanisms.
Genetic lesions that function as dominant negative mutations in microbial systems have long been recognized. It is only relatively recently, however, that similar dominant negative mutations have been implicated as a basis for genetic and neoplastic disorders in vertebrates. We describe here a dissection of the actions of the erbA oncogene protein, an aberrant form of thyroid hormone receptor that acts as a dominant negative inhibitor of other nuclear hormone receptors. We demonstrate that the ErbA oncoprotein interferes with thyroid hormone and trans-retinoic acid receptors by competing for binding to the corresponding response elements. Heterodimerization of the ErbA oncoprotein with these receptors does not play an observable role in repression. In contrast, however, the ErbA oncoprotein does efficiently form a heterodimer with the retinoid X receptor (RXR) class of nuclear hormone receptors; complex formation enhances the DNA-binding properties of the ErbA protein but dramatically interferes with the ability of the RXR component to activate gene expression. Our results indicate that the erbA oncogene may play a previously unanticipated role in neoplasia by interfering with RXR function.
Chen
H W
HW
Department of Microbiology, University of California at Davis 95616.
Privalsky
M L
ML
D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004330:Drosophila; D006801:Humans; D018774:Oncogene Proteins v-erbA; D009857:Oncogenes; D016133:Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic
D018774:Oncogene Proteins v-erbA; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D015682:Retroviridae Proteins, Oncogenic; D013963:Thyroid Hormones; D014157:Transcription Factors; D004247:DNA