Chromosomal instability and tumorigenesis : genetic analysis of the murine spindle checkpoint gene Mps1

The ubiquity of aneuploidy in human cancers, particularly solid tumors, suggests a fundamental link between errors in chromosome segregation and tumorigenesis. The spindle checkpoint ensures accurate chromosome segregation by delaying anaphase onset until all kinetochores achieve bipolar attachment to the mitotic spindle. Abrogation of the mammalian spindle checkpoint can cause chromosomal instability (CIN), the frequent gain or loss of entire chromosomes during cell divisions. While CIN has been proposed to be sufficient to initiate tumorigenesis, no direct evidence has shown that CIN itself is a causal agent for human cancer. To determine if CIN can promote tumor formation, I generated mice containing a conditional mutant allele of the spindle checkpoint kinase MPS1 (MpslA) and induced its expression in thymocytes. I show that MpslA is a partial loss of function allele for spindle checkpoint activation which results in chromosome missegregation in MEFs and embryonic lethality in mice. Expression of MpslA in thymocytes causes sporadic lymphomas and a decrease in thymus size. Strikingly, when MpslA was introduced into a p53 heterozygous background, all mice developed thymomas due to a loss of heterozygosity of the wildtype p53 allele.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Biology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2007

Author dc:creator

• Xie, Stephanie Zhi-Juan

Advisor dc:contributor.advisor

• Peter K. Sorger.

• Biology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/38628

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/38628