Abstract
CCDC6 was originally identified in chimeric genes as caused by chromosomal translocation involving the RET protooncogene in some thyroid tumors. Recognised as a 65 kDa pro-apoptotic phosphoprotein, CCDC6 has been enrolled as an ATM substrate that contribute to protect genome integrity by modulating PP4c activity in response to genotoxic stress. Recently, CCDC6 has been identified as a repressor of CREB1-dependent transcription. Sumoylation has emerged as an important mechanism in transcriptional control. Here, we report the identification and characterization of three sites of sumoylation in CCDC6 (K74, K266 and K424) which are highly conserved in vertebrates. We demonstrate that the post-translational modifications by SUMO2 constrain most of the CCDC6 protein in the cytosol and affect its functional interaction with CREB1 with a decrease of CCDC6 repressive function on CREB1 transcriptional activity. Indeed, the impairment of functional outcome of sumoylated CCDC6 is obtained knocking down all three the sumoylation sites. Interestingly, in thyroid cells the SUMO2-mediated CCDC6 post-translational modifications are induced by Forskolin, a cAMP analog. Signal transduction via the cAMP pathway is known to be ubiquitous and represents a major line of communication between many organisms and their environment. We believe that CCDC6 could be an important player in the dynamics of cAMP signaling by fine regulating CREB1 transcriptional activity in normal and transformed thyroid cells.
Highlights
The genome locus for CCDC6 is commonly rearranged in various tumours
Even though the function of CCDC6 wild type is still under investigation, we described the involvement of this gene in apoptosis and the ability of its truncated mutant 1-101, that corresponds to the portion of CCDC6 included in RET/PTC1, to act as dominant negative on nuclear localization and on the wildtype CCDC6-induced apoptosis [14]
CCDC6 is a Substrate for small ubiquitin-like modifiers (SUMO) Modification In order to investigate if CCDC6 could be post-translational modified by SUMO proteins we performed a sumoylation assay
Summary
The genome locus for CCDC6 is commonly rearranged in various tumours. CCDC6-RET fusions have been originally found in about 20% of human papillary thyroid carcinoma, generating the oncogene RET/PTC1 [1;2]. RET/PTCs are chimeric genes generated by the fusion of the RET tyrosine kinase (TK) domain with the 59 terminal region of other genes. There are at least 15 types of RET/PTC rearrangements involving RET and 10 different genes. In RET/PTC1 the fusion occurs with the CCDC6 gene [1] following a chromosomal inversion [inv (10) (q11.2q21)] [5]. Unidentifed CCDC6-RET fusions have been recently described in lung adenocarcinoma [6]. CCDC6 has been reported to be rearranged with genes different from RET in thyroid and nonthyroid tumours [7;8]
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