Thyroid hormone activation of transcription is potentiated by activators of cAMP-dependent protein kinase.
We characterized the cross-talk between activators of protein kinase A (PKA) and thyroid hormone (T3) in T3 receptor (TR)-mediated transcription. U937 cells were cotransfected with a plasmid expressing the TR and a reporter plasmid containing a T3 response element (TRE) oriented either as a direct repeat or as a palindrome upstream of the thymidine kinase promoter linked to the chloramphenicol acetyltransferase gene. T3 activated transcription by 10-fold. T3 response was potentiated 2.5-3-fold by activators of PKA, but an activator of protein kinase C or of guanylate kinase was ineffective. In the absence of T3, activators of PKA had no effect on transcription. TR heterodimerization with the retinoid X receptor may facilitate T3/PKA cross-talk because coexpression of the retinoid X receptor potentiated cross-talk. Synergy was not observed in JEG-3, F9, CV-1, HeLa, L929, and HTC cells, indicating that it may require cell-specific factors. Synergy required the DNA- and ligand-binding domains, but not the amino-terminal domain, indicating that T3- and TRE-induced conformational changes on the TR are essential for cross-talk. PKA phosphorylated the TR in vitro, suggesting that, like other nuclear receptors, the TR is a target for PKA. These results imply that PKA cross-talks with T3 at the level of the TRE-bound TR, enhancing its transcriptional activity in a cell-specific manner.
Leitman
D C
DC
Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco 94143-0540, USA.
Costa
C H
CH
Graf
H
H
Baxter
J D
JD
Ribeiro
R C
RC
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D051528:Guanylate Kinases; D006801:Humans; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014284:Triiodothyronine / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; C016276:8-bromocyclic GMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases; D006152:Cyclic GMP