Functional specificity of two hormone response elements present on the human apoA-II promoter that bind retinoid X receptor alpha/thyroid receptor beta heterodimers for retinoids and thyroids: synergistic interactions between thyroid receptor beta and upstream stimulatory factor 2a.
DNA binding and mutagenesis in vitro established that the -67/-55 region of the apoA-II (apolipoprotein A-II) promoter contains a thyroid HRE (hormone response element), which strongly binds RXRalpha (retinoid X receptor alpha)/T(3)Rbeta (thyroid receptor beta) heterodimers and weakly T(3)Rbeta homodimers, but does not bind other homo- or heterodimers of RXRalpha or orphan nuclear receptors. Transactivation was abolished by point mutations in the thyroid HRE. In co-transfection experiments of HEK-293 (human embryonic kidney 293) cells, the -911/+29 human apoA-II promoter was transactivated strongly by RXRalpha/T(3)Rbeta heterodimers in the presence of RA (9- cis retinoic acid) or T(3) (tri-iodothyronine). Homopolymeric promoters containing either three copies of the -73/-40 (element AIIAB) or four copies of the -738/-712 (element AIIJ) apoA-II promoter could be transactivated by RXRalpha/T(3)Rbeta heterodimers in COS-7 cells only in the presence of T(3) or RA respectively. RXRalpha/T(3)Rbeta heterodimers and USF2a (upstream stimulatory factor 2a) synergistically transactivated the -911/+29 apoA-II promoter in the presence of T(3). USF2a also enhanced the activity of a GAL4-T(3)Rbeta fusion protein in the presence of T(3) and suppressed the activity of a GAL4-RXRalpha fusion protein in the presence of RA. These findings suggest a functional specificity of the two HREs of the apoA-II promoter for retinoids and thyroids, which is modulated by synergistic or antagonistic interactions between RXRalpha/T(3)Rbeta heterodimers and the ubiquitous transcription factor USF2a.
Hatzivassiliou
Eudoxia
E
Biomedical Sciences Research Center Al. Fleming, Institute of Immunology, 14-16 Al. Fleming Str., Vari GR-16672, Greece.
Koukos
George
G
Ribeiro
Agnes
A
Zannis
Vassilis
V
Kardassis
Dimitris
D
D000077556:Alitretinoin; D000818:Animals; D016633:Apolipoprotein A-II / Q000235:genetics*; D001665:Binding Sites; D019556:COS Cells; D002460:Cell Line; D004268:DNA-Binding Proteins; D019281:Dimerization; D004357:Drug Synergism; D006801:Humans; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D020218:Response Elements; D047488:Retinoid X Receptors; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014212:Tretinoin / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism; D014284:Triiodothyronine / Q000494:pharmacology*; D051720:Upstream Stimulatory Factors
D016633:Apolipoprotein A-II; D004268:DNA-Binding Proteins; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; D014280:Triglycerides; D051720:Upstream Stimulatory Factors; D014284:Triiodothyronine; D000077556:Alitretinoin; D014212:Tretinoin