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A Complex Deoxyribonucleic Acid Response Element in the Rat Ca²⁺/Calmodulin-Dependent Protein Kinase IV Gene 5'-Flanking Region Mediates Thyroid Hormone Induction and Chicken Ovalbumin Upstream Promoter Transcription Factor 1 Repression

Molecular Endocrinology Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Departments of Medicine and Physiology, UCLA School of Medicine, Los Angeles, California 90073

Address all correspondence and requests for reprints to: Gregory A. Brent, M.D., Molecular Endocrinology Laboratory Building 114, Room 230, 11301 Wilshire Boulevard, Los Angeles, California 90073. E-mail: gbrent{at}ucla.edu.

Ca²⁺/calmodulin-dependent protein kinase IV (CaMKIV) is regulated by T₃ in a time- and concentration-dependent manner in the developing rat brain and plays an important role in neuronal-specific gene regulation. T₃ 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 T₃ responsiveness and bound thyroid hormone receptor (TR), retinoic acid receptor (RAR), and chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TF1). T₃ and RA treatment stimulated the CaMKIV hormone response element. Cotransfection of a COUP-TF1 expression vector repressed the T₃ 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 T₃ and COUP-TF1 regulation of CaMKIV expression.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  RARα  |  RXRα  |  COUP-TFI

Ligands:   9-cis-Retinoic acid  |  Thyroid hormone

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