Sodium butyrate selectively alters thyroid hormone receptor gene expression in GH3 cells.
High-affinity binding of thyroid hormone (T3) to nuclear receptors influences the transcriptional rate of specific genes. The carboxylic acid, sodium butyrate, is known to reduce nuclear binding of T3 in GH3 rat pituitary cels, and this effect correlates with inhibition of T3 responsiveness. Incubation of GH3 cells with 10 mM, but not 1 mM, sodium butyrate abolishes induction of growth hormone gene expression by T3. The relationship between thyroid hormone receptor (TR) depletion and inhibition of T3 action was further investigated by determining the effects of sodium butyrate on TR gene expression. GH3 cells contain mRNAs encoding at least three thyroid hormone receptors (TRs alpha 1, beta 1, and beta 2), as well as a related non-T3 binding repressor or T3 action (c-erbA alpha 2). Remarkably, 10 mM sodium butyrate reduces TR beta 2 mRNA levels by greater than 95% in the presence or absence of T3. The down-regulation of TR beta 2 mRNA occurs at a concentration of sodium butyrate between 5 and 10 mM and is maximal by 8 h of treatment. In contrast, TR beta 1 mRNA levels are unchanged. Furthermore, sodium butyrate has little effect on the mRNAs encoding TR alpha 1 and c-erbA alpha 2. Nuclear run-on assays indicated that sodium butyrate depletes TR beta 2 mRNA by rapidly repressing TR beta 2 gene transcription. In the presence of the transcriptional inhibitor, actinomycin D, the half-life of TR beta 2 mRNA was approximately 3 h in the presence or absence of sodium butyrate. Thus, the reduction in TR number induced by sodium butyrate is likely to be due to the transcriptionally mediated reduction in TR beta 2 mRNA. These data suggest that TR beta 2 has an important physiological role in the regulation of growth hormone gene expression by T3.
Lazar
M A
MA
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104.
D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D002460:Cell Line; D003609:Dactinomycin / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D013006:Growth Hormone / Q000235:genetics; D007700:Kinetics; D010911:Pituitary Neoplasms; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000187:drug effects / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D014284:Triiodothyronine / Q000494:pharmacology
D002087:Butyrates; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D020148:Butyric Acid; D003609:Dactinomycin; D013006:Growth Hormone