Identification of a thyroid hormone response element in the promoter region of the rat lipocalin-type prostaglandin D synthase (beta-trace) gene.
We have previously reported that mRNA levels for the rat lipocalin-type prostaglandin (PG) D synthase/beta-trace (PGDS) gene, the enzyme responsible for the production of PGD2 in the central nervous system, are regulated by thyroid hormone in vivo. In this study, we describe the identification of a thyroid hormone (T3) response element (T3RE) in the 5'-flanking region of the rat PGDS gene. By radioimmunoprecipitation of genomic fragments using thyroid hormone receptor (TR) protein and specific anti-TR antibodies, gel-shift, foot-printing, mutational analysis, and transactivation assays we have identified a spaced four imperfect direct repeat (DR4) element, GGTTCACTTCAGGGTA (positions -586/-571), which functions as a T3RE when fused to a heterologous promoter. Our results suggest that thyroid hormone regulates the expression of the rat lipocalin-type PGDS gene through this element. Remarkably, the element identified also confers regulation by retinoic acid. Giving the important roles proposed for the PGDS enzyme and its product, PGD2, the major PG in the mammalian brain, the altered expression of the PGDS gene may contribute to the deleterious effects of hypothyroidism in the central nervous system.
García-Fernández
L F
LF
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Arturo Duperier 4, 28029 Madrid, Spain.
Urade
Y
Y
Hayaishi
O
O
Bernal
J
J
Muñoz
A
A
D020121:5' Untranslated Regions; D000209:Acute-Phase Proteins; D000818:Animals; D001483:Base Sequence; D001609:Beta-Globulins / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics*; D005796:Genes; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D000071068:Lipocalin-2; D054834:Lipocalins; D008969:Molecular Sequence Data; D015513:Oncogene Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011518:Proto-Oncogene Proteins; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000235:genetics; D011988:Receptors, Thyroid Hormone / Q000235:genetics; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation; D014284:Triiodothyronine / Q000378:metabolism* / Q000502:physiology*
D020121:5' Untranslated Regions; D000209:Acute-Phase Proteins; D001609:Beta-Globulins; D002352:Carrier Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014284:Triiodothyronine; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase