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This version published online on August 8, 2002
Molecular Endocrinology, doi:10.1210/me.2001-0324
A more recent version of this article appeared on November 1, 2002
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Submitted on November 30, 2001
Accepted on July 23, 2002

A Complex DNA 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

Yan-Yun Liu1 and Gregory A. Brent1*

1 Molecular Endocrinology Laboratory VA Greater Los Angeles Healthcare System Departments of Medicine and Physiology UCLA School of Medicine MS#ME-01{ndash}0324 Revised 6/28/02

* To whom correspondence should be addressed. E-mail: gbrent{at}ucla.edu.

Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) is regulated by triiodothyronine (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 I (COUP-TF1). T3 and RA treatment stimulated the CaMKIV hormone response element. Co-transfection of a COUP-TF1 expression vector repressed the T3 response and augmented the RA response. Mutational analysis identified 3 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/RXR binding, but modestly augmented RAR/RXR 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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