Although age is the largest single risk factor for cancer, the molecular genetic basis underlying the interrelationship between cancer and aging remains largely unknown. Filling this gap in knowledge is important for understanding both cancer and aging. BubR1, a core mitotic checkpoint component that regulates proper chromosome segregation, has emerged as a key determinant of both cancer and aging. Mutant mice carrying BubR1 hypomorphic alleles (BubR1H/H mice) that produce low amounts of the protein accumulate aneuploid cells and are susceptible to tumors. These animals also develop various progeroid and early aging-related phenotypes, including short lifespan, growth retardation, cataracts, sarcopenia, subdermal fat loss, reduced dermal thickness, and impaired wound healing. Furthermore, mutations in BubR1 have been associated with mosaic variegated aneuploidy (MVA), a rare human syndrome that is characterized by aneuploidization, cancer, and several progeroid traits, many of which overlap with those seen in BubR1H/H mice. Importantly, BubR1 abundance declines in various mouse tissues with chronological aging. A ubiquitously expressed BubR1 transgene that prevents this decline preserves chromosomal integrity, reduces tumorigenesis, extends lifespan, and delays age-related deterioration of several tissues. The objective of this application is to resolve the molecular pathway governed by BubR1 and to determine how changes in BubR1 abundance alter the rate with which cancer and age-related pathologies develop. Based on persuasive preliminary data we hypothesize that uncontrolled APC/CCdc20 E3 ubiquitin ligase activity that results from BubR1 insufficiency plays a central role in cancer susceptibility and premature aging, and that sustained levels of BubR1 attenuate the development of cancer and age-related disorders by maintaining proper control of APC/CCdc20. We will test this hypothesis by pursuing three specific aims. In the first aim, we will determine how mechanistically BubR1 over- expression protects against cancer and aging. In the second aim, we will determine how uncontrolled APC/CCdc20 activity drives cancer and premature aging. In the third aim, we will establish the role of BubR1 kinase activity in controlling APC/CCdc20 activity, cancer and aging. The expected overall impact of the proposed work is that it will fundamentally advance our mechanistic understanding of a prominent mitotic check- point protein implicated in two major human health problems, cancer and aging, and will provide insight into how contrasting changes in BubR1 abundance alter the rate with which cancer and age-related pathologies develop. This knowledge will pave the way towards transformative clinical interventions for treating or preventing a broad spectrum of human cancers and age-related diseases that limit healthspan, in addition to conceptually advancing the fields of mitosis, cancer and aging.

Public Health Relevance

The proposed research is relevant to public health because it is expected to fundamentally advance our mechanistic understanding of a multifunctional mitotic regulator, BubR1 that is implicated in two major human health problems, cancer and aging. We expect this knowledge to pave the way towards transformative clinical interventions for treating or preventing a broad spectrum of human cancers and age-related diseases that limit healthspan.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA096985-13
Application #
8688161
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Hildesheim, Jeffrey
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
van Deursen, Jan M (2014) The role of senescent cells in ageing. Nature 509:439-46
North, Brian J; Rosenberg, Michael A; Jeganathan, Karthik B et al. (2014) SIRT2 induces the checkpoint kinase BubR1 to increase lifespan. EMBO J 33:1438-53
Childs, Bennett G; Baker, Darren J; Kirkland, James L et al. (2014) Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep 15:1139-53
Baker, Darren J; Weaver, Robbyn L; van Deursen, Jan M (2013) p21 both attenuates and drives senescence and aging in BubR1 progeroid mice. Cell Rep 3:1164-74
Ricke, Robin M; van Deursen, Jan M (2013) Aneuploidy in health, disease, and aging. J Cell Biol 201:11-21
Baker, Darren J; Dawlaty, Meelad M; Wijshake, Tobias et al. (2013) Increased expression of BubR1 protects against aneuploidy and cancer and extends healthy lifespan. Nat Cell Biol 15:96-102
Baker, Darren J; Wijshake, Tobias; Tchkonia, Tamar et al. (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232-6
Ricke, Robin M; van Deursen, Jan M (2011) Aurora B hyperactivation by Bub1 overexpression promotes chromosome missegregation. Cell Cycle 10:3645-51
Ricke, Robin M; van Deursen, Jan M (2011) Correction of microtubule-kinetochore attachment errors: mechanisms and role in tumor suppression. Semin Cell Dev Biol 22:559-65
Ricke, Robin M; Jeganathan, Karthik B; van Deursen, Jan M (2011) Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation. J Cell Biol 193:1049-64

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