# Mechanisms Controlling BubR1 Regulation of Cancer and Aging

> **NIH NIH K01** · CREIGHTON UNIVERSITY · 2020 · $123,903

## Abstract

Abstract:
The goal of this proposal is to elucidate the molecular mechanisms governing BubR1 protein abundance and
function, and its role in the regulation of tumorigenesis and aging. Aging is the single greatest risk factor for
cancer development, yet the mechanistic basis driving this interrelationship remains largely undefined. BubR1,
a serine/threonine protein kinase, is involved in the spindle assembly checkpoint (SAC) to ensure faithful
chromosome segregation during mitosis, and therefore is intimately linked to genomic integrity and cancer.
Interestingly, recent studies have implicated BubR1 in the aging process where BubR1 abundance has been
shown to decline in a variety of tissues as mammals age. Mice engineered to express low levels of BubR1
from birth die within a year, exhibiting increased senescence, premature aging phenotypes and an increased
susceptibility to cancer, whereas mice overexpressing BubR1 have an extended lifespan with reduction in age-
related diseases and cancer development. Senescence is believed to be largely tumor-suppressive and
prevent cancer in young individuals. However, in aged individuals senescent cells can contribute to age-related
cancer development. Therefore, BubR1 may play a pivotal role in the interrelationship between aging and
cancer given that BubR1 suppresses both senescence and tumorigenesis. Previously, we identified an
acetylation-dependent mechanism regulating BubR1 protein stability, where SIRT2 prevents degradation of
BubR1 through deacetylation, leading to lifespan extension of a BubR1 premature aging mouse model.
Furthermore, BubR1 protein levels in aged animals can be restored to youthful levels by stimulating SIRT2
activity through induction of NAD+ levels. These results suggest that the age-related decline in BubR1 levels
can be reversed, potentially alleviating age-related diseases including cancer. Therefore, we hypothesize that
BubR1 is a key tumor suppressor, and its loss with age increases cancer susceptibility. In this proposal, we
plan to: 1) elucidate the physiological role of BubR1 post translational modifications during aging and calorie
restriction and their impact on mitotic progression and tumorigenesis; and 2) determine the mechanisms
regulating BubR1 protein abundance and function during aging. These studies will elucidate how regulation of
BubR1 by post-translational modifications controls mitotic progression and tumorigenesis during aging as well
as to identify mechanisms through which BubR1 declines with age and controls the aging processes. Given
that aging poses the largest single risk factor for developing cancer, elucidating the molecular details governing
the physiological role of BubR1 in cancer and aging will provide mechanistic understanding of the
interrelationship between aging and cancer development, as well as identify possible therapeutic strategies to
treat age-related diseases.

## Key facts

- **NIH application ID:** 9897456
- **Project number:** 5K01AG052627-05
- **Recipient organization:** CREIGHTON UNIVERSITY
- **Principal Investigator:** Brian J. North
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $123,903
- **Award type:** 5
- **Project period:** 2016-09-30 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897456

## Citation

> US National Institutes of Health, RePORTER application 9897456, Mechanisms Controlling BubR1 Regulation of Cancer and Aging (5K01AG052627-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9897456. Licensed CC0.

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