title: Role of Epac and protein kinase A in thyrotropin-induced gene expression in primary thyrocytes.
abstract: cAMP pathway activation by thyrotropin (TSH) induces differentiation and gene expression in thyrocytes. We investigated which partners of the cAMP cascade regulate gene expression modulations: protein kinase A and/or the exchange proteins directly activated by cAMP (Epac). Human primary cultured thyrocytes were analysed by microarrays after treatment with the adenylate cyclase activator forskolin, the protein kinase A (PKA) activator 6-MB-cAMP and the Epac-selective cAMP analog 8-pCPT-2'-O-Me-cAMP (007) alone or combined with 6-MB-cAMP. Profiles were compared to those of TSH. Cultures treated with the adenylate cyclase- or the PKA activator alone or the latter combined with 007 had profiles similar to those induced by TSH. mRNA profiles of 007-treated cultures were highly distinct from TSH-treated cells, suggesting that TSH-modulated gene expressions are mainly modulated by cAMP and PKA and not through Epac in cultured human thyroid cells. To investigate whether the Epac-Rap-RapGAP pathway could play a potential role in thyroid tumorigenesis, the mRNA expressions of its constituent proteins were investigated in two malignant thyroid tumor types. Modulations of this pathway suggest an increased Rap pathway activity in these cancers independent from cAMP activation.
authors.affiliation: Institute of Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles, 808 Route de Lennik, B-1070 Brussels, Belgium.
authors.forename: Wilma C G
authors.initials: WC
authors.lastname: van Staveren
authors.forename: Sandrine
authors.initials: S
authors.lastname: Beeckman
authors.forename: Gil
authors.initials: G
authors.lastname: Tomás
authors.forename: Geneviève
authors.initials: G
authors.lastname: Dom
authors.forename: Aline
authors.initials: A
authors.lastname: Hébrant
authors.forename: Laurent
authors.initials: L
authors.lastname: Delys
authors.forename: Marjolein J
authors.initials: MJ
authors.lastname: Vliem
authors.forename: Christophe
authors.initials: C
authors.lastname: Trésallet
authors.forename: Guy
authors.initials: G
authors.lastname: Andry
authors.forename: Brigitte
authors.initials: B
authors.lastname: Franc
authors.forename: Frédérick
authors.initials: F
authors.lastname: Libert
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Dumont
authors.forename: Carine
authors.initials: C
authors.lastname: Maenhaut
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D003994:Bucladesine / Q000031:analogs & derivatives / Q000494:pharmacology; D002277:Carcinoma; D002291:Carcinoma, Papillary; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D020536:Enzyme Activators / Q000494:pharmacology; D015870:Gene Expression; D020869:Gene Expression Profiling; D020662:Guanine Nucleotide Exchange Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D061251:Primary Cell Culture; D015398:Signal Transduction; D000077273:Thyroid Cancer, Papillary; D065646:Thyroid Carcinoma, Anaplastic; D013961:Thyroid Gland / Q000473:pathology*; D013964:Thyroid Neoplasms / Q000378:metabolism; D013972:Thyrotropin / Q000494:pharmacology / Q000502:physiology*; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C473217:8-(4-chloro-phenylthio)-2'-O-methyladenosine-3'-5'-cyclic monophosphate; D020536:Enzyme Activators; D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; C442864:RAPGEF4 protein, human; C002373:monobutyryl cyclic AMP; D005576:Colforsin; D003994:Bucladesine; D013972:Thyrotropin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020827:rap1 GTP-Binding Proteins; D000262:Adenylyl Cyclases