CCAAT/Enhancer-Binding Protein-Homologous Protein Expression and Transcriptional Activity Are Regulated by 3′,5′-Cyclic Adenosine Monophosphate in Thyroid Cells

Martine Pomerance, Daniel Carapau, Françoise Chantoux, Michaël Mockey, Claude Correze, Jacques Francon, Jean-Paul Blondeau
2003 Molecular Endocrinology  
The cAMP pathway activates p38-MAPKs in the FRTL-5 rat thyroid cell line, contributing to the increased expression of the Na+/I-symporter (NIS) mRNA. This study investigates the cAMP-dependent expression and transcriptional activity of the p38-MAPK substrate C/EBP homologous protein (CHOP). CHOP is expressed in the rat thyroid gland and in confluent PCCL3 and FRTL-5 cells. In FRTL-5 cells, TSH withdrawal induced a rapid downregulation of CHOP that could be prevented by forskolin. Moreover, TSH
more » ... nd forskolin were able to reinduce CHOP expression. The use of pharmacological inhibitors indicated that cAMP-induced CHOP expression was dependent on protein kinase A (PKA), mammalian target of rapamycin pathway, and reactive oxygen species. Transfection of a CHOP trans-reporting system revealed strong stimulation of the transcriptional activity of CHOP by forskolin, by chlorophenylthio-cAMP, and by the catalytic subunit of PKA. CHOP transcriptional activity was significantly reduced by the p38-MAPK inhibitor SB203580, by transfection of a dominant negative variant of p38α-MAPK, or by mutation of two serine residues in CHOP targeted by p38-MAPKs. Finally, cAMP-induced NIS mRNA expression was higher in FRTL-5 cells stably transfected with CHOP cDNA than in control cells. Likewise, the activity of the NIS promoter was higher in cells over-expressing CHOP than in control cells. These findings suggest that the stimulation of CHOP expression and transcriptional activity by the cAMP pathway may contribute to the regulation of genes involved in thyroid cell differentiation.
doi:10.1210/me.2002-0400 pmid:12907753 fatcat:3mbicvkvdfbibd3os2hx3gsmka