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This version published online on October 24, 2002
Molecular Endocrinology, doi:10.1210/me.2002-0107
A more recent version of this article appeared on January 1, 2003
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Submitted on March 20, 2002
Accepted on October 10, 2002

Hormone-dependent repression of the E2F-1 gene by thyroid hormone receptors

Maria Nygård1, Gunilla M. Wahlström1, Maria V. Gustafsson1, Yasuhito M. Tokumoto1, and Maria Bondesson1*

1 Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, S-171 77 Stockholm, Sweden. MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London, London WC1E 6BT, UK Molecular Endocrinology 2002 In press

* To whom correspondence should be addressed. E-mail: maria.bondesson{at}cmb.ki.se.

Thyroid hormone induces differentiation of many different tissues in mammals, birds and amphibians. The different tissues all differentiate from proliferating precursor cells, and the normal cell cycle is suspended while cells undergo differentiation. We have investigated how thyroid hormone affects the expression of the E2F-1 protein, a key transcription factor that controls G1 to S-phase transition. We show that during thyroid hormone-induced differentiation of embryonic carcinoma cells and of oligodendrocyte precursor cells, the levels of E2F-1 mRNA and E2F-1 protein decrease. This is caused by the thyroid hormone receptor regulating the transcription of the E2F-1 gene. The thyroid hormone receptor binds directly to a negative thyroid hormone response element called the Z-element, in the E2F-1 promoter. When bound, the thyroid hormone receptor activates transcription in the absence of ligand, but represses transcription in the presence of ligand. In addition, liganded thyroid hormone receptor represses transcription of the S-phase-specific DNA polymerase {alpha}, thymidine kinase and dihydropholate reductase genes. These results suggest that thyroid hormone-induced withdrawal from the cell cycle takes place through the repression of S-phase genes. We suggest that this is an initial and crucial step in thyroid hormone-induced differentiation of precursor cells.
Key words: thyroid hormone • thyroid hormone receptor • E2F-1 • cell proliferation • transcription

NURSA Molecule Pages Link:

Nuclear Receptors:   TRα  |  TRβ  |  NURR1
Ligands:   9-cis-Retinoic acid  |  Thyroid hormone



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