title: Ras oncoprotein disrupts the TSH/CREB signaling upstream adenylyl cyclase in human thyroid cell.
abstract: Activating mutations in RAS genes and p21 Ras overactivation are common occurrences in a variety of human tumors. p21 Ras oncoproteins deregulate a number of signaling pathways, dedifferentiating the thyroid cell, and negatively regulating the expression of thyroid specific genes. In rat thyroid cells, Ras oncoproteins inhibit the TSH pathway by reducing PKA activity and thus the expression of thyroid specific genes, while in mouse melanocytes, Ras oncoproteins reduce the αMSH-stimulated cAMP signaling by increasing the expression of the phosphodiesterase-4B. Given these cell-dependent differences, we investigated if and how the TSH/CREB pathway is modulated by Ras oncoprotein in a human thyroid cell line. CREB phosphorylation was stimulated by TSH and forskolin in TAD-2 cells. Ras(V12) expression negatively regulated the TSH-stimulated CREB phosphorylation but was ineffective on forskolin-stimulated CREB phosphorylation. Phosphodiesterase inhibition by IBMX enhanced TSH-stimulated CREB phosphorylation, but did not restore TSH-stimulated CREB phosphorylation inhibited by Ras oncoprotein. These data indicate that Ras oncoprotein disrupts the TSH/CREB pathway, upstream adenylyl cyclase, and highlight the existence of mechanisms of interaction between Ras and the cAMP pathway different in human and in rat thyroid cells.
authors.affiliation: Department of Medicine and Surgery, University of Salerno, Baronissi 84081, Salerno, Italy; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: Marcella
authors.initials: M
authors.lastname: Salzano
authors.forename: Eleonora
authors.initials: E
authors.lastname: Russo
authors.forename: Salvatore
authors.initials: S
authors.lastname: Salzano
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bifulco
authors.forename: Mario
authors.initials: M
authors.lastname: Vitale
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000008:administration & dosage; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism; D013972:Thyrotropin / Q000378:metabolism*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D013972:Thyrotropin; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D016283:Proto-Oncogene Proteins p21(ras); D000262:Adenylyl Cyclases; D015056:1-Methyl-3-isobutylxanthine