Hormone-dependent repression of the E2F-1 gene by thyroid hormone receptors.
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 (TR) regulating the transcription of the E2F-1 gene. The TR binds directly to a negative thyroid hormone response element, called the Z-element, in the E2F-1 promoter. When bound, the TR activates transcription in the absence of ligand but represses transcription in the presence of ligand. In addition, liganded TR 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.
Nygård
Maria
M
Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Wahlström
Gunilla M
GM
Gustafsson
Maria V
MV
Tokumoto
Yasuhito M
YM
Bondesson
Maria
M
D000818:Animals; D018236:Carcinoma, Embryonal; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D006801:Humans; D051379:Mice; D009836:Oligodendroglia / Q000166:cytology; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D014284:Triiodothyronine / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000166:cytology
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D014157:Transcription Factors; D014284:Triiodothyronine