CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1.
RET/papillary thyroid carcinoma 1 (PTC1) oncogene is frequently activated in human PTCs. It is characterized by the fusion of the intracellular kinase-encoding domain of RET to the first 101 amino acids of CCDC6. The aim of our work is to characterize the function of the CCDC6 protein to better understand the function of its truncation, that results in the loss of the expression of one allele, in the process of thyroid carcinogenesis. Here, we report that CCDC6 interacts with CREB1 and represses its transcriptional activity by recruiting histone deacetylase 1 and protein phosphatase 1 proteins at the CRE site of the CREB1 target genes. Finally, we show an increased CREB1 phosphorylation and activity in PTCs carrying the RET/PTC1 oncogene. Consistently, an increased expression of two known CREB1 target genes, AREG and cyclin A, was observed in this subgroup of thyroid papillary carcinomas. Therefore, the repression of CREB1 activity by CCDC6 has a critical function in the development of human thyroid papillary carcinomas carrying RET/PTC1 activation.
Leone
V
V
Istituto di Endocrinologia ed Oncologia Sperimentale del CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia di Napoli, Università degli Studi di Napoli Federico II, Naples, Italy.
Mansueto
G
G
Pierantoni
G M
GM
Tornincasa
M
M
Merolla
F
F
Cerrato
A
A
Santoro
M
M
Grieco
M
M
Scaloni
A
A
Celetti
A
A
Fusco
A
A
D066258:Amphiregulin; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000502:physiology*; D066255:EGF Family of Proteins; D006023:Glycoproteins / Q000235:genetics; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D012097:Repressor Proteins / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000209:etiology*; D014158:Transcription, Genetic
C587848:AREG protein, human; D066258:Amphiregulin; C088832:CCDC6 protein, human; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D003598:Cytoskeletal Proteins; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; D012097:Repressor Proteins; D011505:Protein-Tyrosine Kinases; C093573:ret-PTC fusion oncoproteins, human; D054645:Protein Phosphatase 1; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1