title: Thyroid hormone regulation of transcription factors involved in malic enzyme gene expression.
abstract: The mechanisms by which triiodothyronine (T3) regulates gene transcription are inadequately understood. In order to examine the effect of T3 on transcriptional mechanisms, we utilized several techniques to characterize trans-acting factors which interact with cis-regulatory elements of the promoter for the T3-responsive rat malic enzyme gene. Transcription of deletion mutants of the promoter by HeLa extracts revealed the existence of three cis-regulatory elements at -144 to -123, -70 to -50, and -30 to +5 (relative to the cap site at +1). DNase I footprinting disclosed the presence of proteins which bound to each of these regions. Gel mobility shift assays showed that specific binding of liver nuclear proteins to two of these regions (-144/-114 and -76/-47) was diminished in hypothyroid and elevated in hyperthyroid rats. Similar but less marked effects of T3 on the binding of kidney (a T3-responsive tissue) nuclear proteins to the -76/-47 and cap site regions were observed while binding of testis (a T3-nonresponsive tissue) nuclear proteins was unaffected by T3 treatment. Changes in the magnitude and time course of binding of liver proteins to this promoter correlated closely with previously documented T3-induced increases in the hepatic malic enzyme gene transcription rate. These results are consistent with a model in which the regulation of malic enzyme gene transcription by T3 in responsive tissues is mediated in part by hormone-induced increases in the binding of trans-acting factors to cis-regulatory elements.
authors.affiliation: Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892.
authors.forename: K J
authors.initials: KJ
authors.lastname: Petty
authors.forename: H
authors.initials: H
authors.lastname: Morioka
authors.forename: T
authors.initials: T
authors.lastname: Mitsuhashi
authors.forename: V M
authors.initials: VM
authors.lastname: Nikodem
mesh_terms: D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000032:analysis; D004247:DNA / Q000378:metabolism; D003850:Deoxyribonuclease I; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D006980:Hyperthyroidism / Q000378:metabolism; D007037:Hypothyroidism / Q000378:metabolism; D007668:Kidney / Q000648:ultrastructure; D007700:Kinetics; D008099:Liver / Q000648:ultrastructure; D008291:Malate Dehydrogenase / Q000235:genetics*; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D011919:Rats, Inbred Strains; D012045:Regulatory Sequences, Nucleic Acid; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014284:Triiodothyronine / Q000494:pharmacology*
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; D014284:Triiodothyronine; D004247:DNA; D008291:Malate Dehydrogenase; D003850:Deoxyribonuclease I