The oncoprotein P75gag-v-erbA represses thyroid hormone induced transcription only via response elements containing palindromic half-sites.
The v-erbA oncoprotein P75gag-v-erbA, derived from the thyroid hormone receptor alpha (TR alpha), functions as a transdominant transcriptional repressor. The mechanism by which P75gag-v-erbA acts is however poorly characterized. Here, we show that repression of TR alpha mediated transcription by P75gag-v-erbA in transformed erythroblasts is dependent on the structure of the thyroid hormone response element to which it binds. A very efficient repression was seen with hormone response elements having half-sites organized as everted repeats (ER), whereas repression was inefficient with directly repeated half-sites (DR). Promoters containing half-sites organized as an inverted palindrome (IR) gave an intermediate repression. Although P75gag-v-erbA failed to associate with the ligand binding domain of retinoid X (RXR) receptor in a two-hybrid test, the oncoprotein in nuclear extracts from transformed cells heterodimerised quantitatively with RXR upon binding to response elements of the DR type. On the other hand, both RXR/P75gag-v-erb heterodimers and other types of dimers formed on ER elements. P75gag-v-erbA also failed to bind to elements that contained only one half-site in vivo and in vitro. The data demonstrate that P75gag-v-erbA represses gene expression efficiently as a dimer, and suggest that thyroid hormone responsive genes that may be targets for the action of the oncoprotein are repressed most efficiently if they contain elements of the ER type.
Wahlström
G M
GM
Department of Cellular and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
Harbers
M
M
Vennström
B
B
D001483:Base Sequence; D001704:Biopolymers; D004268:DNA-Binding Proteins / Q000378:metabolism; D015683:Gene Products, gag / Q000378:metabolism / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D018774:Oncogene Proteins v-erbA / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors; D013963:Thyroid Hormones / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*; D014407:Tumor Cells, Cultured
D001704:Biopolymers; D004268:DNA-Binding Proteins; D015683:Gene Products, gag; D009838:Oligodeoxyribonucleotides; D018774:Oncogene Proteins v-erbA; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013963:Thyroid Hormones; D014157:Transcription Factors