Vitamin D interferes with transactivation of the growth hormone gene by thyroid hormone and retinoic acid.
The thyroid hormone, retinoic acid (RA), and vitamin D regulate gene expression by binding to similar receptors which act as ligand-inducible transcription factors. Incubation of pituitary GH4C1 cells with nanomolar concentrations of vitamin D markedly reduces the response of the rat growth hormone mRNA to thyroid hormone triiodothyronine (T3) and RA. The stimulation of growth hormone gene expression by both ligands is mediated by a common hormone response element (TREGH) present in the 5'-flanking region of the gene, and the inhibition caused by vitamin D is due to transcriptional interference of the vitamin D receptor on this DNA element. No inhibition of the basal promoter activity by the vitamin was observed. The response to T3 and RA of a heterologous promoter containing this element, the palindromic T3- and RA-responsive sequence TREPAL, or a direct repeat of the same motif is also inhibited by vitamin D. In contrast, vitamin D strongly induces the activity of constructs containing a vitamin D response element, and neither T3 nor RA reduces vitamin D-mediated transactivation. Transfection with an expression vector for the retinoid X receptor alpha (RXR alpha) increases transactivation by T3 and RA but does not abolish the inhibition caused by the vitamin. Gel retardation experiments show that the vitamin D receptor (VDR) as a heterodimer with RXR weakly binds to the T3- and RA-responsive elements. Additionally, VDR displaces binding of T3 and RA receptors in a dose-dependent manner. Our data suggest the formation of TR-VDR and RAR-VDR heterodimers with RXR. The fact that the same response element mediates opposite effects of at least four different nuclear receptors provides a greater complexity and flexibility of the transcriptional responses to their ligands.
Instituto de Investigaciones Biomedicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
P
P
Garcia-Villalba
A M
AM
Jimenez-Lara
A
A
Aranda
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002762:Cholecalciferol / Q000494:pharmacology*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D013006:Growth Hormone / Q000235:genetics*; D008969:Molecular Sequence Data; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018167:Receptors, Calcitriol / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*; D014284:Triiodothyronine / Q000494:pharmacology*
D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014284:Triiodothyronine; D002762:Cholecalciferol; D014212:Tretinoin; D013006:Growth Hormone; D004247:DNA