Survivin safeguards chromosome numbers and protects from aneuploidy independently from p53

Molecular Cancer

Research

Masaaki Tatsuka¹  Ralf Wiedemuth²  Katrin Töpfer²  Achim Temme²  Gabriele Schackert²  Barbara Klink³  Evelin Schröck³ 

[1] Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima, Japan;Department of Neurosurgery, Section Experimental Neurosurgery/Tumor Immunology, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307, Dresden, Germany;Institute for Clinical Genetics, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307, Dresden, Germany;

关键词: Survivin;    p53;    p21;    ATM;    DNA-PK;   

DOI  :  10.1186/1476-4598-13-107

 received in 2013-12-06, accepted in 2014-05-02,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundSurvivin, a member of the inhibitor of apoptosis (IAP) gene family, has a dual role in mitosis and in apoptosis. It is abundantly expressed in every human tumor, compared with normal tissues. During mitosis Survivin assembles with the chromosomal passenger complex and regulates chromosomal segregation. Here, we aim to explore whether interference with the mitotic function of Survivin is linked to p53-mediated G1 cell cycle arrest and affects chromosomal stability.MethodsIn this study, we used HCT116, SBC-2, and U87-MG and generated corresponding isogenic p53-deficient cells. Retroviral vectors were used to stably knockdown Survivin. The resulting phenotype, in particular the mechanisms of cell cycle arrest and of initiation of aneuploidy, were investigated by Western Blot analysis, confocal laser scan microscopy, proliferation assays, spectral karyotyping and RNAi.ResultsIn all cell lines Survivin-RNAi did not induce instant apoptosis but caused polyplodization irrespective of p53 status. Strikingly, polyploidization after knockdown of Survivin resulted in merotelic kinetochore spindle assemblies, γH2AX-foci, and DNA damage response (DDR), which was accompanied by a transient p53-mediated G1-arrest. That p53 wild type cells specifically arrest due to DNA damage was shown by simultaneous inhibition of ATM and DNA-PK, which abolished induction of p21waf/cip. Cytogenetic analysis revealed chromosomal aberrations indicative for DNA double strand break repair by the mechanism of non-homologous end joining (NHEJ), only in Survivin-depleted cells.ConclusionOur findings suggest that Survivin plays an essential role in proper amphitelic kinetochore-spindle assembly and that constraining Survivin’s mitotic function results in polyploidy and aneuploidy which cannot be controlled by p53. Therefore, Survivin critically safeguards chromosomal stability independently from p53.

【 授权许可】

Unknown   
© Wiedemuth et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.