Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bennett D . (2005). Transcriptional control by chromosome-associated protein phosphatase-1. Biochem Soc Trans 33 (Pt 6): 1444–1446.
Berasain C, Castillo J, Perugorría MJ, Prieto J, Avila MA . (2007). Amphiregulin: a new growth factor in hepatocarcinogenesis. Cancer Lett 254: 30–41.
Canettieri G, Morantte I, Guzmán E, Asahara H, Herzig S, Anderson SD et al. (2003). Attenuation of a phosphorylation-dependent activator by an HDAC-PP1 complex. Nat Struct Biol 10: 175–181.
Celetti A, Cerrato A, Merolla F, Vitagliano D, Vecchio G, Grieco M . (2004). H4(D10S170), a gene frequently rearranged with RET in papillary thyroid carcinomas: functional characterization. Oncogene 23: 109–121.
De Angelis R, Iezzi S, Bruno T, Corbi N, Di Padova M, Floridi A et al. (2003). Functional interaction of the subunit 3 of RNA polymerase II (RPB3) with transcription factor-4 (ATF4). FEBS Lett 547: 15–19.
De Martino I, Visone R, Wierinckx A, Palmieri D, Ferraro A, Cappabianca P et al. (2009). HMGA proteins up-regulate CCNB2 gene in mouse and human pituitary adenomas. Cancer Res 69: 1844–1850.
Dettori T, Frau DV, Garcia JL, Pierantoni G, Lee C, Hernandez JM et al. (2004). Comprehensive conventional and molecular cytogenetic characterization of B-CPAP, a human papillary thyroid carcinoma-derived cell line. Cancer Genet Cytogenet 151: 171–177.
Drechsler M, Hildebrandt B, Kündgen A, Germing U, Royer-Pokora B . (2007). Fusion of H4/D10S170 to PDGFRbeta in a patient with chronic myelomonocytic leukemia and long-term responsiveness to imatinib. Ann Hematol 86: 353–354.
Fabien N, Fusco A, Santoro M, Barbier Y, Dubois PM, Paulin C . (1994). Description of a human papillary thyroid carcinoma cell line. Morphologic study and expression of tumoral markers. Cancer 73: 2206–2212.
Fedele M, Pentimalli F, Baldassarre G, Battista S, Klein-Szanto AJ, Kenyon L et al. (2005). Transgenic mice over-expressing the wild-type form of the HMGA1 gene develop mixed growth hormone/prolactin cell pituitary adenomas and natural killer cell lymphomas. Oncogene 24: 3427–3435.
Gao J, Siddoway B, Huang Q, Xia H . (2009). Inactivation of CREB mediated gene transcription by HDAC8 bound protein phosphatase. Biochem Biophys Res Commun 379: 1–5.
Gonzalez GA, Montminy MR . (1989). Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59: 675–680.
Grieco M, Santoro M, Berlingieri MT, Melillo RM, Donghi R, Bongarzone I et al. (1990). PTC is a novel rearranged form of the RET proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60: 557–563.
Grieco M, Cerrato A, Santoro M, Fusco A, Melillo RM, Vecchio G . (1994). Cloning and characterization of H4(D10S170), a gene involved in RET rearrangements in vivo. Oncogene 9: 2531–2535.
Hagiwara M, Alberts A, Brindle P, Meinkoth J, Feramisco J, Deng T et al. (1992). Transcriptional attenuation following cAMP induction requires PP-1-mediated dephosphorylation of CREB. Cell 70: 105–113.
Han Y, Haines CJ, Feng HL . (2007). Role(s) of the serine/threonine protein phosphatase 1 on mammalian sperm motility. Arch Androl 53: 169–177.
Hu XD, Huang Q, Roadcap DW, Shenolikar SS, Xia H . (2006). Actin-associated neurabin-protein phosphatase-1 complex regulates hippocampal plasticity. J Neurochem 98: 1841–1851.
Kimura T, Van Keymeulen A, Golstein J, Fusco A, Dumont JE, Roger PP . (2001). Regulation of thyroid cell proliferation by TSH and other factors: a critical evaluation of in vitro models. Endocr Rev 22: 631–656.
Klumpp S, Krieglstein J . (2002). Serine/threonine protein phosphatases in apoptosis. Curr Opin Pharmacol 2: 458–462.
Kondo T, Ezzat S, Asa SL . (2006). Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 6: 292–306.
Kulkarni S, Heath C, Parker S, Chase A, Iqbal A, Pocock F et al. (2000). Fusion of H4/D10S170 to the platelet-derived growth factor receptor β in BCR-ABL-negative myeloproliferative disorders with a t(5;10)(q33;q21). Cancer Res 60: 3592–3598.
Luciani P, Buci L, Conforti B, Tonacchera M, Agretti P, Elisei R et al. (2003). Expression of cAMP response element-binding protein and sodium iodide symporter in benign non-functioning and malignant thyroid tumours. Eur J Endocrinol 148: 579–586.
Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK . (2001). Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1: 194–202.
Merolla F, Pentimalli F, Pacelli R, Vecchio G, Fusco A, Grieco M et al. (2007). Involvement of H4(D10S170) protein in ATM-dependent response to DNA damage. Oncogene 26: 6167–6175.
Pallante P, Federico A, Berlingieri MT, Bianco M, Ferraro A, Forzati F et al. (2008). Loss of the CBX7 gene expression correlates with a highly malignant phenotype in thyroid cancer. Cancer Res 68: 6770–6778.
Pierantoni GM, Rinaldo C, Esposito F, Mottolese M, Soddu S, Fusco A . (2006). High Mobility Group A1 (HMGA1) proteins interact with p53 and inhibit its apoptotic activity. Cell Death Differ 13: 1554–1563.
Pierantoni GM, Esposito F, Giraud S, Bienvenut WV, Diaz JJ, Fusco A . (2007). Identification of new high mobility group A1 associated proteins. Proteomics 7: 3735–3742.
Pierotti MA, Santoro M, Jenkins RB, Sozzi G, Bongarzone I, Grieco M et al. (1992). Characterization of an inversion on the long arm of chromosome 10 juxtaposing D10S170 and RET and creating the oncogenic sequence RET/PTC. Proc Natl Acad Sci USA 89: 1616–1620.
Puxeddu E, Zhao G, Stringer JR, Medvedovic M, Moretti S, Fagin JA . (2005). Characterization of novel non-clonal intrachromosomal rearrangements between the H4 and PTEN genes (H4/PTEN) in human thyroid cell lines and papillary thyroid cancer specimens. Mutat Res 570: 17–32.
Santoro M, Dathan NA, Berlingieri MT, Bongarzone I, Paulin C, Pierotti MA et al. (1994). Molecular characterization of RET/PTC 3: a novel rearranged version of the RET proto-oncogene in a human thyroid papillary carcinoma. Oncogene 9: 509–516.
Santoro M, Chiappetta G, Cerrato A, Salvatore D, Zhang L, Manzo G et al. (1996). Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 12: 1821–1826.
Santoro M, Melillo RM, Fusco A . (2006). RET/PTC activation in papillary thyroid carcinoma. Eur J Endocrinol 155: 645–653.
Schwaller J, Anastasiadou E, Cain D, Kutok J, Woyiski S, Willimas IR et al. (2001). CCDC6, a gene frequently rearranged in papillary thyroid carcinomas, is fused to the platelet-derived growth factor receptor β gene in atypical chronic myeloid leukaemia with t(5;10)(q33;q22). Blood 97: 3910–3918.
Sheils OM, O′Leary JJ, Sweeney EC. (2000). Assessment of ret/PTC-1 rearrangements in neoplastic thyroid tissue using TaqMan RT-PCR. J Pathol 192: 32–36.
Talamo F, D′Ambrosio C, Arena S, Del Vecchio P, Ledda L, Zehender G et al. (2003). Proteins from bovine tissues and biological fluids: defining a reference electrophoresis map for liver, kidney, muscle, plasma and red blood cells. Proteomics 3: 440–460.
Terrak M, Kerff F, Langsetmo K, Tao T, Dominguez R . (2004). Structure basis of protein phosphatase1 regulation. Nature 429: 780–784.
Trinkle-Mulcahy L, Lamond AI . (2006). Mitotic phosphatases: no longer silent partners. Curr Opin Cell Biol 18: 623–631.
Viglietto G, Chiappetta G, Martinez-Tello FJ, Fukunaga FH, Tallini G, Rigopoulou D et al. (1995). RET/PTC oncogene activation is an early event in thyroid carcinogenesis. Oncogene 11: 1207–1210.
Virshup DM, Shenolikar S . (2009). From promiscuity to precision: protein phosphatases get a makeover. Mol Cell 33: 537–545.
Wang B, Zhang P, Wei Q . (2008). Recent progress on the structure of Ser/Thr protein phosphatases. Sci China C Life Sci 51: 487–494.
Acknowledgements
This work was supported by grants from the Associazione Italiana Ricerca sul Cancro (AIRC) and from the Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) (MERIT and PRIN 2008 CCPKRP_002). We are grateful to Konstantina Vergadou (Scientific Communication) for editing the text and Mario Berardone for artwork.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Oncogene website
Rights and permissions
About this article
Cite this article
Leone, V., Mansueto, G., Pierantoni, G. et al. CCDC6 represses CREB1 activity by recruiting histone deacetylase 1 and protein phosphatase 1. Oncogene 29, 4341–4351 (2010). https://doi.org/10.1038/onc.2010.179
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2010.179
Keywords
This article is cited by
-
OLFM4-RET fusion is an oncogenic driver in small intestine adenocarcinoma
Oncogene (2022)
-
The circ_FAM53B-miR-183-5p-CCDC6 axis modulates the malignant behaviors of papillary thyroid carcinoma cells
Molecular and Cellular Biochemistry (2022)
-
The rationale for druggability of CCDC6-tyrosine kinase fusions in lung cancer
Molecular Cancer (2018)
-
Genomic analysis of a four-way t(4;11;22;10) associated with MLL-AF4 in an adult acute lymphoblastic leukemia
Annals of Hematology (2012)