A complex deoxyribonucleic acid response element in the rat Ca(2+)/calmodulin-dependent protein kinase IV gene 5'-flanking region mediates thyroid hormone induction and chicken ovalbumin upstream promoter transcription factor 1 repression.
Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV) is regulated by T(3) in a time- and concentration-dependent manner in the developing rat brain and plays an important role in neuronal-specific gene regulation. T(3) treatment, but not retinoic acid (RA), stimulated endogenous CaMKIV mRNA 5-fold in mouse embryonic stem (ES) cells differentiated into neurons. We localized a region -750 to -700 in the CaMKIV gene 5'-flanking region that conferred T(3) responsiveness and bound thyroid hormone receptor (TR), retinoic acid receptor (RAR), and chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TF1). T(3) and RA treatment stimulated the CaMKIV hormone response element. Cotransfection of a COUP-TF1 expression vector repressed the T(3) response and augmented the RA response. Mutational analysis identified three half-sites arranged in a direct repeat (AB) and overlapping inverted repeat (BC), required for functional induction and receptor binding. TR and RAR bound predominantly to the BC portion of the element and COUP-TF1 to the AB region, with a close correlation of binding and functional studies. COUP-TF1 binding did not influence TR/retinoid X receptor binding but modestly augmented RAR/retinoid X receptor binding. A single element confers T(3) and COUP-TF1 regulation of CaMKIV expression.
Liu
Yan-Yun
YY
Molecular Endocrinology Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073, USA.
Brent
Gregory A
GA
D024506:5' Flanking Region / Q000235:genetics*; D000375:Aging; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000201:enzymology* / Q000254:growth & development; D051838:COUP Transcription Factor I; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D002478:Cells, Cultured; D002645:Chickens; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010047:Ovalbumin / Q000235:genetics*; D010957:Plasmids; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D013963:Thyroid Hormones / Q000096:biosynthesis*; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D014284:Triiodothyronine / Q000494:pharmacology*
D051838:COUP Transcription Factor I; D004268:DNA-Binding Proteins; C497590:Nr2f1 protein, mouse; C497591:Nr2f1 protein, rat; D011994:Recombinant Proteins; D013963:Thyroid Hormones; D014157:Transcription Factors; D014284:Triiodothyronine; D010047:Ovalbumin; D011494:Protein Kinases; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517685:Camk4 protein, mouse; C517686:Camk4 protein, rat