title: Modulation of the transcriptional activity of thyroid hormone receptors by the tumor suppressor p53.
abstract: Thyroid hormone nuclear receptors (TRs) are ligand-dependent transcriptional factors that regulate growth, differentiation, and development. The molecular mechanisms by which TRs mediate these effects are unclear. One prevailing hypothesis suggests that TRs may cooperate with other transcriptional factors to mediate their biological effects. In this study, we tested this hypothesis by examining whether the activity of TRs is modulated by the tumor suppressor p53. p53 is a nuclear protein that regulates gene expression via sequence-specific DNA binding and/or direct protein-protein interaction. We found that the human TR subtype beta 1 (h-TR beta 1) physically interacted with p53 via its DNA binding domain. As a result of this physical interaction, binding of h-TR beta 1 to its hormone response elements either as homodimer or as a heterodimer with the retinoic X receptor was inhibited by p53 in a concentration-dependent manner. In transfected cells, wild-type p53 repressed the hormone-dependent transcriptional activation of h-TR beta 1. In contrast, mutant p53 either had no effect or activated the transcriptional activity of h-TR beta 1 depending on the type of hormone response elements. These results indicate the gene regulating activity of TRs was modulated by p53, suggesting that the cross talk between these two transcriptional factors may play an important role in the biology of normal and cancer cells.
authors.affiliation: Gene Regulation Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
authors.forename: N
authors.initials: N
authors.lastname: Yap
authors.forename: C L
authors.initials: CL
authors.lastname: Yu
authors.forename: S Y
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D002522:Chlorocebus aethiops; D004926:Escherichia coli; D005786:Gene Expression Regulation; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D018168:Receptors, Retinoic Acid / Q000302:isolation & purification / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000302:isolation & purification / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000378:metabolism; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000302:isolation & purification / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000302:isolation & purification / Q000378:metabolism*
chemical_list: D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D015500:Chloramphenicol O-Acetyltransferase; D005982:Glutathione Transferase