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The Thyroid Hormone Receptor- (TR) Gene Encoding TR1 Controls Deoxyribonucleic Acid Damage-Induced Tissue Repair

Université de Lyon, Université Claude Bernard Lyon 1, Ecole Normale Supérieure de Lyon, Institut National de la Recherche Agronomique, Centre National de la Recherche Scientifique, Institut de Génomique Fonctionnelle de Lyon, 69364 Lyon Cedex 07, France

Address all correspondence and requests for reprints to: Michelina Plateroti, Institut de Génomique Fonctionnelle de Lyon, Ecole Normale Supérieure de Lyon, 46 allée d’Italie, 69364 Lyon Cedex 07, France. E-mail: Michela.Plateroti{at}ens-lyon.fr.

The thyroid hormone (TH) controls, via its nuclear receptor, TH receptor-1 (TR1), intestinal crypt cell proliferation in the mouse. In order to understand whether this receptor also plays a role in intestinal regeneration after DNA damage, we applied a protocol of -ray irradiation and monitored cell proliferation and apoptosis at several time points. In wild-type mice, the dose of 8 Gy induced cell cycle arrest and apoptosis in intestinal crypts a few hours after irradiation. This phenomenon reverted 48 h after irradiation. TR^0/0 mutant mice displayed a constant low level of proliferating cells and a high apoptosis rate during the period of study. At the molecular level, in TR^0/0 animals we observed a delay in the p53 phosphorylation induced by DNA damage. In our search for the expression of the protein kinases responsible for p53 phosphorylation upon irradiation, we have focused on DNA-dependent protein kinase catalytic subunit (DNA-PKcs). The number of cells expressing DNA-PKcs in crypts remained high 48 h after irradiation, specifically in TR mutants. Altogether, in TR^0/0 animals the rate of apoptosis in crypt cells remained high, apparently due to an elevated number of cells still presenting DNA damage. In conclusion, the TR gene plays a role in crypt cell homeostasis by regulating the rate of cell renewal and apoptosis induced by DNA damage.

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Nuclear Receptors:   TRα