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Chromosomal instability in mouse embryonic fibroblasts null for the transcriptional co‐repressor Ski
Author(s) -
Marcelain Katherine,
Armisen Ricardo,
Aguirre Adam,
Ueki Nobuhide,
Toro Jessica,
Colmenares Clemencia,
Hayman Michael J
Publication year - 2012
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22733
Subject(s) - mitosis , microbiology and biotechnology , mitotic catastrophe , metaphase , biology , anaphase , spindle checkpoint , chromosome instability , chromosome segregation , aneuploidy , embryonic stem cell , cell cycle , spindle apparatus , genetics , chromosome , cell division , cell , gene
Abstract Ski is a transcriptional regulator that has been considered an oncoprotein given its ability to induce oncogenic transformation in avian model systems. However, studies in mouse and in some human tumor cells have also indicated a tumor suppressor activity for this protein. We found that Ski −/− mouse embryo fibroblasts exhibit high levels of genome instability, namely aneuploidy, consistent with a tumor suppressor function for Ski. Time‐lapse microscopy revealed lagging chromosomes and chromatin/chromosome bridges as the major cause of micronuclei (MN) formation and the subsequent aneuploidy. Although these cells arrested in mitosis after treatment with spindle disrupting drugs and exhibited a delayed metaphase/anaphase transition, spindle assembly checkpoint (SAC) was not sufficient to prevent chromosome missegregation, consistent with a weakened SAC. Our in vivo analysis also showed dynamic metaphase plate rearrangements with switches in polarity in cells arrested in metaphase. Importantly, after ectopic expression of Ski the cells that displayed this metaphase arrest died directly during metaphase or after aberrant cell division, relating SAC activation and mitotic cell death. This increased susceptibility to undergo mitosis‐associated cell death reduced the number of MN‐containing cells. The presented data support a new role for Ski in the mitotic process and in maintenance of genetic stability, providing insights into the mechanism of tumor suppression mediated by this protein. J. Cell. Physiol. 227: 278–287, 2012. © 2011 Wiley Periodicals, Inc.