Thyroid Hormone Receptor α1 Directly Controls Transcription of the β-Catenin Gene in Intestinal Epithelial Cells

• DOI: 10.1128/mcb.26.8.3204-3214.2006
• Publication Date: 2006-03-31T01:46:06Z
• Authors: Michelina Plateroti; Elsa Kress; Jun Ichirou Mori; Jacques Samarut
• Keywords: 0301 basic medicine; Chromatin Immunoprecipitation; Transcription, Genetic; proliferation; [SDV]Life Sciences [q-bio]; 610; nuclear receptors; Electrophoretic Mobility Shift Assay; Transfection; Mice; 03 medical and health sciences; Chlorocebus aethiops; Intestine, Small; FACTEUR DE TRANSCRIPTION; Animals; [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology; [INFO]Computer Science [cs]; intestine; development; Cells, Cultured; beta Catenin; Cell Proliferation; Mice, Knockout; Epithelial Cells; DNA; Sequence Analysis, DNA; thyroid hormone; AMPHIBIEN; Introns; 3. Good health; INTESTIN; Animals, Newborn; Gene Expression Regulation; COS Cells; EXPRESSION GENIQUE; INTESTINAL EPITHELIAL CELLS; TUMEUR; Thyroid Hormone Receptors alpha

Thyroid hormones, T3 and T4, are known regulators of intestine development. The best characterized example is the remodeling of the gastrointestinal tract during amphibian metamorphosis. Thyroid hormones act via nuclear receptors, the TRs, which are T3-dependent transcription factors. We previously showed that intestinal epithelial cell proliferation is controlled by thyroid hormones and the TRalpha gene. To analyze the mechanisms responsible, we studied the expression of genes belonging to and/or activated by the Wnt/beta-catenin pathway, a major actor in the control of physiological and pathological epithelial proliferation in the intestine. We show that T3-TRalpha1 controls the transcription of the beta-catenin gene in an epithelial cell-autonomous way. This is parallel to positive regulation of proliferation-controlling genes such as type D cyclins and c-myc, known targets of the Wnt/beta-catenin. In addition, we show that the regulation of the beta-catenin gene is direct, as TR binds in vitro and in chromatin in vivo to a specific thyroid hormone-responsive element present in intron 1 of this gene. This is the first report concerning in vivo transcriptional control of the beta-catenin gene. As Wnt/beta-catenin plays a crucial role in intestinal tumorigenesis, our observations open a new perspective on the study of TRs as potential tumor inducers.