Research Papers:
FBXW7 and USP7 regulate CCDC6 turnover during the cell cycle and affect cancer drugs susceptibility in NSCLC
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Abstract
Francesco Morra1,2,*, Chiara Luise1,*, Francesco Merolla1,3, Ina Poser4, Roberta Visconti1, Gennaro Ilardi3, Simona Paladino2, Hiroyuki Inuzuka5, Gianluca Guggino6, Roberto Monaco7, David Colecchia8, Guglielmo Monaco6, Aniello Cerrato1, Mario Chiariello8, Krista Denning9, Pier Paolo Claudio10, Stefania Staibano3 and Angela Celetti1
1 Istituto per l’Endocrinologia e l’Oncologia Sperimentale “Gaetano Salvatore”, CNR, Napoli, Italy
2 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Federico II, Napoli, Italy
3 Dipartimento di Scienze Biomediche Avanzate, Università Federico II, Napoli, Italy
4 Max Plank Institute, MPI-CBG Dresden, Germany
5 Harvard Medical School, Beth Israel Deaconess Medical Center, MA, USA
6 UOC Chirurgia Toracica, Azienda Ospedaliera di Rilievo Nazionale “A.Cardarelli”, Napoli, Italy
7 UOC Anatomia Patologica, Azienda Ospedaliera di Rilievo Nazionale “A.Cardarelli”, Napoli, Italy
8 Istituto Toscano Tumori, Core Research Laboratory, Siena, Italy
9 Department of Pathology, Joan C. Edwards Cancer Center, Huntington, WV, USA
10 Department of Biochemistry and Microbiology & Dept. of Surgery, Marshall University, Joan C. Edwards Cancer Center, Huntington, WV, USA
* These authors have contributed equally to this work
Correspondence to:
Angela Celetti, email:
Keywords: CCDC6, FBXW7, USP7, mitotic kinases, cisplatinum
Received: January 20, 2015 Accepted: March 03, 2015 Published: March 30, 2015
Abstract
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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