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 (T-3) in T-3 receptor (TR)-mediated transcr iption. U937 cells mere cotransfected with a plasmid expressing the TR and a reporter plasmid containing a T-3 response element (TRE) orient ed either as a direct repeat or as a palindrome upstream of the thymid ine kinase promoter linked to the chloramphenicol acetyltransferase ge ne. T-3 activated transcription by 10-fold. T-3 response was potentiat ed 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 T-3, acti vators of PKA had no effect on transcription. TR heterodimerization wi th the retinoid X receptor may facilitate T-3/PKA cross-talk because c oexpression of the retinoid X receptor potentiated cross-talk. Synergy was not observed in JEG-3, F9, CV-1, HeLa, L929, and HTC cells, indic ating that it may require cell-specific factors. Synergy required the DNA- and ligand-binding domains, but not the amino-terminal domain, in dicating that T-3- and TRE-induced conformational changes on the TR ar e essential for cross-talk. PKA phosphorylated the TR in vitro, sugges ting that, like other nuclear receptors, the TR is a target for PKA. T hese results imply that PICA cross-talks with T-3 at the level of the TRE-bound TR, enhancing its transcriptional. activity in a cell-specif ic manner.