SirT1, the mammalian ortholog of yeast Sir2, regulates a variety of cellular processes in mammalian cells, such as cellular stress response and energy metabolism, contributing to possible anti-aging effects. On the other hand, SirT1 activity is also important for tumor cell growth and survival, possibly due to SirT1's anti- apoptotic effect. Therefore, SirT1 has important implications in both aging and cancer, making SirT1 activity a double-edged sword that requires tight regulation. However, the regulation of SirT1 is unclear. In order to understand the regulation of SirT1, we set out to identify SirT1-associated proteins. Through tandem affinity purification and mass spectrum analysis, we have identified deleted in breast cancer-1 (DBC1) as a SirT1- associated protein. The DBC1 gene localizes to a region (8p21) that is frequently deleted in breast cancers;and loss of DBC1 expression has been detected in some breast and lung cancer cell lines. However, the causal relationship between loss of DBC1 and tumorigenesis has not been established. The cellular functions of DBC1 protein are also unclear. Our preliminary results suggest that DBC1 directly interacts with SirT1 and inhibits SirT1 activity. Downregulation of DBC1 potentiates SirT1-dependent inhibition of apoptosis in response to DNA damage. In addition, loss of DBC1 promotes tumorigenesis in the presence of carcinogens. Based on these observations, we hypothesize that DBC1 negatively regulates SirT1, thereby affecting DNA damage response, aging and tumorigenesis. To build on our previous observations, we now propose the following specific aims: 1. Investigate SirT1-dependent and SirT1-independent function of DBC1. 2. Investigate the regulation of SirT1-DBC1 interaction following DNA damage. 3. Use DBC1 knockout mice to explore the physiological role of DBC1 in aging and tumorigenesis. Results from these studies will not only shed new light on the regulation of SirT1, but also provide important insight into the molecular mechanisms of aging and cancer.

Public Health Relevance

The protein deacetylase SirT1 is linked to both aging and cancer. However, the regulation of SirT1 is unclear. We will investigate the regulation of SirT1 by DBC1, which will provide important insights into the molecular mechanism of aging and cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129344-05
Application #
8408813
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Salnikow, Konstantin
Project Start
2009-01-01
Project End
2014-06-30
Budget Start
2013-01-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$285,879
Indirect Cost
$96,680
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Oi, N; Yuan, J; Malakhova, M et al. (2015) Resveratrol induces apoptosis by directly targeting Ras-GTPase-activating protein SH3 domain-binding protein 1. Oncogene 34:2660-71
Qin, Bo; Gao, Bowen; Yu, Jia et al. (2013) Ataxia telangiectasia-mutated- and Rad3-related protein regulates the DNA damage-induced G2/M checkpoint through the Aurora A cofactor Bora protein. J Biol Chem 288:16139-44
Yuan, Jian; Luo, Kuntian; Liu, Tongzheng et al. (2012) Regulation of SIRT1 activity by genotoxic stress. Genes Dev 26:791-6
Escande, Carlos; Chini, Claudia C S; Nin, Veronica et al. (2010) Deleted in breast cancer-1 regulates SIRT1 activity and contributes to high-fat diet-induced liver steatosis in mice. J Clin Invest 120:545-58
Kim, Ja-Eun; Chen, Junjie; Lou, Zhenkun (2009) p30 DBC is a potential regulator of tumorigenesis. Cell Cycle 8:2932-5
Yuan, Jian; Minter-Dykhouse, Katherine; Lou, Zhenkun (2009) A c-Myc-SIRT1 feedback loop regulates cell growth and transformation. J Cell Biol 185:203-11
Yuan, Jian; Pu, Mintie; Zhang, Zhiguo et al. (2009) Histone H3-K56 acetylation is important for genomic stability in mammals. Cell Cycle 8:1747-53