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Ras Oncoprotein Disrupts the TSH/CREB Signaling Upstream Adenylyl Cyclase in Human Thyroid Cell
Author(s) -
Salzano Marcella,
Russo Eleonora,
Salzano Salvatore,
Bifulco Maurizio,
Vitale Mario
Publication year - 2014
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24672
Subject(s) - creb , forskolin , adenylyl cyclase , phosphorylation , signal transduction , camp dependent pathway , endocrinology , medicine , ibmx , biology , phosphodiesterase , cancer research , microbiology and biotechnology , transcription factor , gene , stimulation , biochemistry , enzyme
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. J. Cell. Physiol. 229: 2137–2141, 2014. © 2014 Wiley Periodicals, Inc.