Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CCDC6 was originally identified in chimeric genes caused by chromosomal translocation involving the RET proto-oncogene in some thryoid tumors mostly upon ionizing radiation exposure. Recognised as a pro-apoptotic phosphoprotein that negatively regulates CREB1-dependent transcription, CCDC6 is an ATM substrate that is responsive to genotoxic stress. Here we report that following genotoxic stress, loss or inactivation of CCDC6 in cancers that carry the CCDC6 fusion, accelerates the dephosphorylation of pH2AX S139, resulting in defective G2 arrest and premature mitotic entry. Moreover, we show that CCDC6 depleted cells appear to repair DNA damaged in a shorter time compared to controls, based on reporter assays in cells. High-troughput proteomic screening predicted the interaction between the CCDC6 gene product and the catalytic subunit of Serin-Threonin Protein Phosphatase 4 (PP4c) recently identified as the evolutionarily conserved pH2AX S139 phosphatase that is activated upon DNA Damage. We describe the interaction between CCDC6 and PP4c and we report the modulation of PP4c enzymatic activity in CCDC6 depleted cells. We discuss the functional significance of CCDC6-PP4c interactions and hypothesize that CCDC6 may act in the DNA Damage Response by negatively modulating PP4c activity. Overall, our data suggest that in primary tumours the loss of CCDC6 function could influence genome stability and thereby contribute to carcinogenesis.
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PMID:Loss of CCDC6, the first identified RET partner gene, affects pH2AX S139 levels and accelerates mitotic entry upon DNA damage. 2265 27

CCDC6 is rearranged in approximately 20% of papillary thyroid carcinomas and some lung cancers participating in the formation of PTC1/ret proto-oncogene oncogene. CCDC6 is involved in the cellular response to DNA damage and is stabilized by ATM-mediated phosphorylation at Thr434. However, the E3 ligase that targets CCDC6 for destruction is unknown. Here, we show that FBXW7 interacts with and targets CCDC6 for ubiquitin-mediated proteasomal degradation. Moreover, FBXW7-mediated CCDC6 degradation is impaired in response to DNA damage. Mechanistically, phosphorylation of CCDC6 at Thr434 by ATM during DNA damage response prevents FBXW6-CCDC6 interaction and FBXW7-mediated CCDC6 degradation. Our results suggest that the involvement of FBXW7 in targeting CCDC6 for destruction will be useful for the establishment of new therapeutic approaches for cancer treatment.
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PMID:FBXW7-mediated degradation of CCDC6 is impaired by ATM during DNA damage response in lung cancer cells. 2310 47

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.
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PMID: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. 2314 46

CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhances tumour progression. In primary tumours, the impaired function of CCDC6 protein has been ascribed to CCDC6 rearrangements and to somatic mutations in several neoplasia. Recently, low levels of CCDC6 protein, in NSCLC, have been correlated with tumor prognosis. However, the mechanisms responsible for the variable levels of CCDC6 in primary tumors have not been described yet.We show that CCDC6 turnover is regulated in a cell cycle dependent manner. CCDC6 undergoes a cyclic variation in the phosphorylated status and in protein levels that peak at G2 and decrease in mitosis. The reduced stability of CCDC6 in the M phase is dependent on mitotic kinases and on degron motifs that are present in CCDC6 and direct the recruitment of CCDC6 to the FBXW7 E3 Ubl. The de-ubiquitinase enzyme USP7 appears responsible of the fine tuning of the CCDC6 stability, affecting cells behaviour and drug response.Thus, we propose that the amount of CCDC6 protein in primary tumors, as reported in lung, may depend on the impairment of the CCDC6 turnover due to altered protein-protein interaction and post-translational modifications and may be critical in optimizing personalized therapy.
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PMID:FBXW7 and USP7 regulate CCDC6 turnover during the cell cycle and affect cancer drugs susceptibility in NSCLC. 2588 23

Cancer, a deadly disease is characterized by abnormal cell growth with the potential to invade to other parts of the body. Most cancers start due to changes at gene level that happen over a person's lifetime when DNA repair system becomes faulty. CCDC6, one of the players in DNA repair system acts as a tumor suppressor gene. It was originally identified in chimeric genes caused by chromosomal translocation involving RET proto-oncogene in some thyroid tumors. Different fusion chimers with different proto-oncogenes like RET are known for CCDC6 which hampered its function. Further, CCDC6 is recognized as a pro-apoptotic phosphoprotein, which is an ATM substrate responsive to genotoxic stress. In this article, we reviewed the published literature to characterize CCDC6 fusions with proto-oncogenes and the role of natural phytochemicals which can potentially alter CCDC6 activity and thus can prove beneficial for cancer patients.
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PMID:CCDC6, a gene product in fusion with different protoncogenes, as a potential chemotherapeutic target. 3090 82