Ccdc6 knock-in mice develop thyroid hyperplasia associated to an enhanced CREB1 activity

// Vincenza Leone 1 , Concetta Langella 1 , Francesco Esposito 1 , Claudio Arra 2 , Giuseppe Palma 2 , Domenica Rea 2 , Orlando Paciello 3 , Francesco Merolla 1 , Davide De Biase 3 , Serenella Papparella 3 , Angela Celetti 1 , Alfredo Fusco 1, 4 1 Istituto per l’Endocrinologia ed Oncologia Sperimentale del CNR e/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli “Federico II”, Naples, Italy 2 Istituto Nazionale per lo Studio e la Cura dei Tumori “Fondazione Giovanni Pascale”, IRCCS, Naples, Italy 3 Department of Pathology and Animal Health, University of Naples “Federico II”, Naples, Italy 4 Instituto Nacional de Câncer - INCA, Rua Andre Cavalcanti, Rio de Janeiro, CEP RJ, Brazil Correspondence to: Alfredo Fusco, e-mail: alfusco@unina.it Keywords: Ccdc6, thyroid, CREB1, knock-in mice Received: February 3, 2015      Accepted: April 14, 2015      Published: April 27, 2015 ABSTRACT 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.