Aneuploidy, an abnormal chromosome number, is a common characteristic of tumor cells, occurring in ~85% of all human cancers. Aneuploidy frequently arises due to errors in chromosome segregation during mitosis. The high prevalence of aneuploidy and mitotic errors in tumor cells prompted the hypothesis that aneuploidy is a cause of tumor genesis. However, this has been difficult to establish. We recently discovered that aneuploidy caused by reduction of the mitosis-specific kinesin-like motor protein CENP- E (CENtromere associated Protein-E) both promotes and suppresses tumors, depending on the context. These findings may have therapeutic implications, particularly since an inhibitor of CENP-E motor activity is currently in clinical trials. The overall goal of this proposal is to define the context-dependent factors that determine whether aneuploidy caused by reduction of CENP-E will promote or suppress tumors. Preliminary studies suggest that tumors with a pre-existing level of genetic instability are susceptible to aneuploidy-mediated tumor suppression, which occurs due to an increase in cell death caused by loss of both copies of one or more essential chromosomes. Experiments in Aim 1 will determine the mechanism(s) of aneuploidy-mediated cell death, and provide a basis to predict which tumors are susceptible.
Aim 2 will determine whether tumors induced by reduction or mutation of the tumor suppressors p53 and APC (Adenomatous Polyposis Coli) are susceptible to aneuploidy-mediated cell death caused by reduction of CENP-E. Previous studies have shown that reduction of CENP-E suppresses tumors in animals lacking the p19ARF tumor suppressor.
Aim 3 will extend preliminary studies that identified a previously unsuspected role for p19ARF in chromosome segregation during mitosis. Together, these experiments will define the characteristics that determine whether a given tumor is susceptible to aneuploidy-mediated tumor suppression and will provide translationally relevant information for use of the CENP-E inhibitor currently in clinical trials.

Public Health Relevance

Cancer is the second most common cause of death in the USA. Errors during cell division are common in cancer cells, but the effects of these errors on tumors are complex. The experiments in this proposal will define how errors during cell division affect tumors, with the ultimate goal of producing clinically useful therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140458-03
Application #
8446524
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Mietz, Judy
Project Start
2011-03-04
Project End
2016-02-29
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2013
Total Cost
$286,622
Indirect Cost
$91,572
Name
University of Wisconsin Madison
Department
Pharmacology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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