Cdt1 Is Differentially Targeted for Degradation by Anticancer Chemotherapeutic Drugs
| Autor: | Zoi Lygerou, Hideo Nishitani, Vassilis Roukos, Panagiotis Kotsantis, Nickolas Karantzelis, Stavros Taraviras, Athanasia Stathopoulou, Chariklia Petropoulou |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
DNA repair
DNA damage Ultraviolet Rays Cancer Treatment lcsh:Medicine Antineoplastic Agents Cell Cycle Proteins Pharmacology medicine.disease_cause DNA replication factor CDT1 Nucleic Acids Neoplasms Molecular Cell Biology medicine Humans Cell cycle DNA replication lcsh:Science Biology Etoposide Cisplatin Multidisciplinary biology lcsh:R DNA Hep G2 Cells Methyl Methanesulfonate Proliferating cell nuclear antigen Tamoxifen Oncology Doxorubicin Cancer cell embryonic structures Proteolysis biology.protein Cancer research Medicine lcsh:Q Fluorouracil Cellular Types Carcinogenesis Cell Division medicine.drug Research Article HeLa Cells |
| Zdroj: | PLoS ONE PLoS ONE, Vol 7, Iss 3, p e34621 (2012) |
| ISSN: | 1932-6203 |
| Popis: | Background Maintenance of genome integrity is crucial for the propagation of the genetic information. Cdt1 is a major component of the pre-replicative complex, which controls once per cell cycle DNA replication. Upon DNA damage, Cdt1 is rapidly targeted for degradation. This targeting has been suggested to safeguard genomic integrity and prevent re-replication while DNA repair is in progress. Cdt1 is deregulated in tumor specimens, while its aberrant expression is linked with aneuploidy and promotes tumorigenesis in animal models. The induction of lesions in DNA is a common mechanism by which many cytotoxic anticancer agents operate, leading to cell cycle arrest and apoptosis. Methodology/Principal Finding In the present study we examine the ability of several anticancer drugs to target Cdt1 for degradation. We show that treatment of HeLa and HepG2 cells with MMS, Cisplatin and Doxorubicin lead to rapid proteolysis of Cdt1, whereas treatment with 5-Fluorouracil and Tamoxifen leave Cdt1 expression unaffected. Etoposide affects Cdt1 stability in HepG2 cells and not in HeLa cells. RNAi experiments suggest that Cdt1 proteolysis in response to MMS depends on the presence of the sliding clamp PCNA. Conclusion/Significance Our data suggest that treatment of tumor cells with commonly used chemotherapeutic agents induces differential responses with respect to Cdt1 proteolysis. Information on specific cellular targets in response to distinct anticancer chemotherapeutic drugs in different cancer cell types may contribute to the optimization of the efficacy of chemotherapy. |
| Databáze: | OpenAIRE |
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