dc.contributor.author | De Bondt, An | |
dc.contributor.author | Kig, Cenk | |
dc.contributor.author | Beullens, Monique | |
dc.contributor.author | Brehmer, Dirk | |
dc.contributor.author | Bollen, Mathieu | |
dc.contributor.author | Beke, Lijs | |
dc.contributor.author | Linders, Joannes T. M. | |
dc.contributor.author | Boens, Shannah | |
dc.contributor.author | Johnson, Christopher N. | |
dc.contributor.author | Van Eynde, Aleyde | |
dc.contributor.author | Meerpoel, Lieven | |
dc.contributor.author | Ogata, Souichi | |
dc.contributor.author | Bashir, Tarig | |
dc.contributor.author | Van den Wyngaert, Ilse | |
dc.contributor.author | Boeckx, An | |
dc.contributor.author | van Heerde, Erika | |
dc.contributor.author | Parade, Marc | |
dc.date.accessioned | 2023-02-21T07:46:59Z | |
dc.date.available | 2023-02-21T07:46:59Z | |
dc.identifier.citation | Beke L., Kig C., Linders J. T. M., Boens S., Boeckx A., van Heerde E., Parade M., De Bondt A., Van den Wyngaert I., Bashir T., et al., "MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells", BIOSCIENCE REPORTS, cilt.35, 2015 | |
dc.identifier.issn | 0144-8463 | |
dc.identifier.other | av_0d5d893e-a994-4446-aa12-8267556b990c | |
dc.identifier.other | vv_1032021 | |
dc.identifier.uri | http://hdl.handle.net/20.500.12627/186100 | |
dc.identifier.uri | https://doi.org/10.1042/bsr20150194 | |
dc.description.abstract | Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and is overexpressed in many cancer cells. The oncogenic function of MELK is attributed to its capacity to disable critical cell-cycle checkpoints and reduce replication stress. Most functional studies have relied on the use of siRNA/shRNAmediated gene silencing. In the present study, we have explored the biological function of MELK using MELK-T1, a novel and selective small-molecule inhibitor. Strikingly, MELK-T1 triggered a rapid and proteasome-dependent degradation of the MELK protein. Treatment of MCF-7 (Michigan Cancer Foundation-7) breast adenocarcinoma cells with MELKT1 induced the accumulation of stalled replication forks and double-strand breaks that culminated in a replicative senescence phenotype. This phenotype correlated with a rapid and long-lasting ataxia telangiectasia-mutated (ATM) activation and phosphorylation of checkpoint kinase 2 (CHK2). Furthermore, MELK-T1 induced a strong phosphorylation of p53 (cellular tumour antigen p53), a prolonged up-regulation of p21 (cyclin-dependent kinase inhibitor 1) and a down-regulation of FOXM1 (Forkhead Box M1) target genes. Our data indicate that MELK is a key stimulator of proliferation by its ability to increase the threshold for DNA-damage tolerance (DDT). Thus, targeting MELK by the inhibition of both its catalytic activity and its protein stability might sensitize tumours to DNA-damaging agents or radiation therapy by lowering the DNA-damage threshold. | |
dc.language.iso | eng | |
dc.subject | Klinik Biyokimya | |
dc.subject | BİYOKİMYA VE MOLEKÜLER BİYOLOJİ | |
dc.subject | Moleküler Biyoloji ve Genetik | |
dc.subject | Yaşam Bilimleri (LIFE) | |
dc.subject | HÜCRE BİYOLOJİSİ | |
dc.subject | Tıp | |
dc.subject | Histoloji-Embriyoloji | |
dc.subject | Yaşam Bilimleri | |
dc.subject | Sitogenetik | |
dc.subject | Sağlık Bilimleri | |
dc.subject | Temel Tıp Bilimleri | |
dc.subject | Temel Bilimler | |
dc.subject | İlaç Keşfi | |
dc.subject | Yapısal Biyoloji | |
dc.subject | Moleküler Biyoloji | |
dc.subject | Hücre Biyolojisi | |
dc.subject | Kanser Araştırmaları | |
dc.subject | Biyokimya | |
dc.subject | Yaşlanma | |
dc.subject | Biyokimya, Genetik ve Moleküler Biyoloji (çeşitli) | |
dc.subject | Genel Biyokimya, Genetik ve Moleküler Biyoloji | |
dc.title | MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells | |
dc.type | Makale | |
dc.relation.journal | BIOSCIENCE REPORTS | |
dc.contributor.department | Univ Louvain , , | |
dc.identifier.volume | 35 | |
dc.contributor.firstauthorID | 4064407 | |