title: Dual regulatory role for thyroid-hormone receptors allows control of retinoic-acid receptor activity.
abstract: Both thyroid hormone (T3) and retinoic acid signal essential steps in development, differentiation and morphogenesis. Specific nuclear receptors for these ligands have recently been cloned. Previously we have noted a close homology between the DNA-binding domains of the epsilon-retinoic acid receptor (RAR-epsilon, also designated RAR-beta), the thyroid hormone receptors and the oestrogen receptor. We have now found that RAR-epsilon is very efficient at inducing transcription from two distinct thyroid-hormone responsive elements (TREs). Transcription induced by ligand-activated RAR-epsilon from a TRE can, however, be repressed by thyroid-hormone receptor in the absence of its ligand. Conversely, in the presence of its ligand, thyroid-hormone receptor will activate transcription from a TRE irrespective of the presence of unbound RAR. The use of hybrid receptors has shown that the DNA-binding domain of RAR is the essential target for inhibition by thyroid-hormone receptors. These data, together with in vitro DNA-binding studies, suggest that thyroid-hormone receptors may have dual regulatory roles: in the presence of hormone they function as TRE-specific transcriptional activators; in the absence of hormone, however, they can function as TRE-specific repressors.
authors.affiliation: Cancer Research Center, La Jolla Cancer Research Foundation, California 92037.
authors.forename: G
authors.initials: G
authors.lastname: Graupner
authors.forename: K N
authors.initials: KN
authors.lastname: Wills
authors.forename: M
authors.initials: M
authors.lastname: Tzukerman
authors.forename: X K
authors.initials: XK
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Pfahl
mesh_terms: D001665:Binding Sites; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D011960:Receptors, Estrogen / Q000502:physiology; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone / Q000502:physiology*; D012045:Regulatory Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D014212:Tretinoin / Q000502:physiology; D014284:Triiodothyronine / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D014157:Transcription Factors; D014284:Triiodothyronine; D014212:Tretinoin