Ccdc6 knock-in mice develop thyroid hyperplasia associated to an enhanced CREB1 activity
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Vincenza Leone1, Concetta Langella1, Francesco Esposito1, Claudio Arra2, Giuseppe Palma2, Domenica Rea2, Orlando Paciello3, Francesco Merolla1, Davide De Biase3, Serenella Papparella3, Angela Celetti1, Alfredo Fusco1,4
1Istituto per l’Endocrinologia ed Oncologia Sperimentale del CNR e/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli “Federico II”, Naples, Italy
2Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale”, IRCCS, Naples, Italy
3Department of Pathology and Animal Health, University of Naples “Federico II”, Naples, Italy
4Instituto Nacional de Câncer - INCA, Rua André Cavalcanti, Rio de Janeiro, CEP RJ, Brazil
Alfredo Fusco, e-mail: [email protected]
Keywords: Ccdc6, thyroid, CREB1, knock-in mice
Received: February 3, 2015 Accepted: April 14, 2015 Published: April 27, 2015
CCDC6 was originally identified upon rearrangement with RET in human thyroid papillary carcinomas generating the RET/PTC1 oncogene. We have previously reported that CCDC6 interacts with CREB1 and represses its transcriptional activity.
Since the function of at least one allele of CCDC6 is lost following RET/PTC1 rearrangements, we aimed at the generation of mice, carrying a CCDC6 mutant gene. Previous studies suggested that the coiled-coil domain of CCDC6, mainly encoded by human exon 2, is required for the protein function. Therefore, we engineered a murine Ccdc6 construct, carrying a deletion of the exon 2, that was able to exert only a mild repression on CREB1 transcriptional activity, with respect to the wild type Ccdc6. Subsequently, we generated Ccdc6-ex2 knock-in mice. These mice developed thyroid hyperplasia associated with an enhanced CREB1 activity and an increased expression of the CREB-1 regulated genes.
These results strongly support a CCDC6 promoting role, ascribed to its functional impairment, in the development of thyroid papillary carcinomas harboring the RET/PTC1 oncogene.
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