title: Novel pathway for thyroid hormone receptor action through interaction with jun and fos oncogene activities.
abstract: Many essential biological pathways, including cell growth, development, and metabolism, are regulated by thyroid hormones (THs). TH action is mediated by intracellular receptors that belong to a large family of ligand-dependent transcription factors, including the steroid hormone and retinoic acid receptors. So far it has been assumed that TH receptors (TRs) regulate gene transcription only through the classical protein-DNA interaction mechanism. Here we provide evidence for a regulatory pathway that allows cross-talk between TRs and the signal transduction pathway used by many growth factors, oncogenes, and tumor promoters. In transient transfection studies, we observed that the oncogenes c-jun and c-fos inhibit TR activities, while TRs inhibit induction of the c-fos promoter and repress AP-1 site-dependent gene activation. A truncated TR that lacks only 17 amino acids from the carboxy terminus can no longer antagonize AP-1 activity. The cross-regulation between TRs and the signal transduction pathway appears to be based on the ability of TRs to inhibit DNA binding of the transcription factor AP-1 in the presence of THs. The constituents of AP-1, c-Jun, and c-Fos, vice versa, can inhibit TR-induced gene activation in vivo, and c-Jun inhibits TR DNA binding in vitro. This novel regulatory pathway is likely to play a major role in growth control and differentiation by THs.
authors.affiliation: Cancer Research Center, La Jolla Cancer Research Foundation, California 92037.
authors.forename: X K
authors.initials: XK
authors.lastname: Zhang
authors.forename: K N
authors.initials: KN
authors.lastname: Wills
authors.forename: M
authors.initials: M
authors.lastname: Husmann
authors.forename: T
authors.initials: T
authors.lastname: Hermann
authors.forename: M
authors.initials: M
authors.lastname: Pfahl
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D016762:Genes, fos; D016758:Genes, jun; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D011988:Receptors, Thyroid Hormone; D004247:DNA; D013755:Tetradecanoylphorbol Acetate