Competition for a unique response element mediates retinoic acid inhibition of vitamin D3-stimulated transcription.
We have identified a novel steroid hormone response element in the avian beta3 integrin promoter. This sequence, comprising three hexameric direct repeat half-sites separated by nine and three nucleotides binds vitamin D receptor (VDR)-retinoid X receptor (RXR) and retinoic acid receptor (RAR)-RXR heterodimers. VDR-RXR binds direct repeats separated by three base pairs, and RAR-RXR recognizes half-sites separated by nine bases, whereas the central half-site interacts with both heterodimers. Retinoic acid and 1, 25-dihydroxyvitamin D3 activate both a genomic fragment including the transcriptional start site and an oligonucleotide containing the three repeats, linked to a heterologous promoter. Co-addition of the steroids produces neither synergy nor an additive effect; rather the result equals that for retinoic acid alone. Scatchard analysis demonstrates that RAR-RXR has greater affinity than VDR-RXR for the composite element. Based on these findings we propose a model in which there is specific, polarity-defined binding of VDR-RXR and RAR-RXR to three half-sites, which form two overlapping steroid response elements, with the central half-site common to both. Our results identify a novel mechanism by which one steroid hormone can modulate the activity of a second, by competing for a shared half-site in a composite response element.
Cao
X
X
Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Teitelbaum
S L
SL
Zhu
H J
HJ
Zhang
L
L
Feng
X
X
Ross
F P
FP
D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D001483:Base Sequence; D001717:Birds; D002762:Cholecalciferol / Q000502:physiology*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D039661:Integrin beta3; D008969:Molecular Sequence Data; D010980:Platelet Membrane Glycoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D018167:Receptors, Calcitriol / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D047488:Retinoid X Receptors; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism*
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D039661:Integrin beta3; D010980:Platelet Membrane Glycoproteins; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D002762:Cholecalciferol; D014212:Tretinoin