Investigation of the role of chromosome missegregation in embryo development and in tumorigenesis

The separation and partitioning of sister chromatids prior to cytokinesis must be tightly regulated to insure that progeny cells receive the correct number of chromosomes. The spindle assembly checkpoint prevents chromosome missegregation by arresting the cell before sister chromatid separation if any one chromatid is not properly attached to the spindle microtubules. Defects in chromosome segregation lead to the creation of aneuploid cells that contain too much or too little genetic material. Some aneuploid cells have gained oncogenes or lost tumor suppressor genes, and these genetic alterations allow the cells to ignore signals that regulate growth and proliferation. A majority of tumors are aneuploid, but it is not yet known whether chromosome instability is a driving force or merely a secondary effect of tumor development. In Chapter 2, I will present work showing that the protein most often altered in colon cancers, Adenomatous Polyposis Coli (AdPC) (Kinzler and Vogelstein 1996), is modified by members of the spindle assembly checkpoint and that a truncating mutation of the AdPC protein leads directly to aneuploidy in mouse cells. Although genetic disruption of any member of the spindle assembly checkpoint signaling cascade has proven lethal for metazoans on both the cellular and organismal level (Basu et al. 1999; Kitagawa and Rose 1999; Dobles et al. 2000; Kalitsis et al. 2000), Chapter 3 will detail the creation and analysis of a Mad2-/- mouse embryonic fibroblast cell line that is viable due to a simultaneous disruption in p53.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Biology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2002

Author dc:creator

• Burds, Aurora A. (Aurora Ann), 1973-

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/1721.1/8382

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/8382