title: Ccdc6 knock-in mice develop thyroid hyperplasia associated to an enhanced CREB1 activity.
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.
authors.affiliation: Istituto 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.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Leone
authors.affiliation: Istituto 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.
authors.forename: Concetta
authors.initials: C
authors.lastname: Langella
authors.affiliation: Istituto 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Esposito
authors.affiliation: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Arra
authors.affiliation: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palma
authors.affiliation: Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale", IRCCS, Naples, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Rea
authors.affiliation: Department of Pathology and Animal Health, University of Naples "Federico II", Naples, Italy.
authors.forename: Orlando
authors.initials: O
authors.lastname: Paciello
authors.affiliation: Istituto 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Merolla
authors.affiliation: Department of Pathology and Animal Health, University of Naples "Federico II", Naples, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: De Biase
authors.affiliation: Department of Pathology and Animal Health, University of Naples "Federico II", Naples, Italy.
authors.forename: Serenella
authors.initials: S
authors.lastname: Papparella
authors.affiliation: Istituto 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.
authors.forename: Angela
authors.initials: A
authors.lastname: Celetti
authors.affiliation: Istituto 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.|Instituto Nacional de Câncer - INCA, Rua André Cavalcanti, Rio de Janeiro, CEP RJ, Brazil.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002277:Carcinoma / Q000235:genetics*; D002291:Carcinoma, Papillary; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts; D055786:Gene Knockout Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D013952:Thymus Hyperplasia / Q000235:genetics*; D000077273:Thyroid Cancer, Papillary; D013961:Thyroid Gland / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: C000607115:CCDC6 protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D003598:Cytoskeletal Proteins; D015514:Oncogene Proteins, Fusion; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse
keywords: CREB1; Ccdc6; knock-in mice; thyroid