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.
| Original language | English |
|---|---|
| Article number | e49298 |
| Journal | PLoS One |
| Volume | 7 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Nov 7 2012 |
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ASJC Scopus subject areas
- Agricultural and Biological Sciences(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
Identification of Sumoylation Sites in CCDC6, the First Identified RET Partner Gene in Papillary Thyroid Carcinoma, Uncovers a Mode of Regulating CCDC6 Function on CREB1 Transcriptional Activity. / Luise, Chiara; Merolla, Francesco; Leone, Vincenza; Paladino, Simona; Sarnataro, Daniela; Fusco, Alfredo; Celetti, Angela.
In: PLoS One, Vol. 7, No. 11, e49298, 07.11.2012.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Identification of Sumoylation Sites in CCDC6, the First Identified RET Partner Gene in Papillary Thyroid Carcinoma, Uncovers a Mode of Regulating CCDC6 Function on CREB1 Transcriptional Activity
AU - Luise, Chiara
AU - Merolla, Francesco
AU - Leone, Vincenza
AU - Paladino, Simona
AU - Sarnataro, Daniela
AU - Fusco, Alfredo
AU - Celetti, Angela
PY - 2012/11/7
Y1 - 2012/11/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84868684272&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84868684272&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0049298
DO - 10.1371/journal.pone.0049298
M3 - Article
C2 - 23145146
AN - SCOPUS:84868684272
VL - 7
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 11
M1 - e49298
ER -