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The Role of Deleted in Breast Cancer 1 (DBC1) in SirT1 Regulation and Tumorigenesis
Tumor Cell Biology I
The Sir2 protein deacetylase regulates life span in various lower organisms. The mammalian ortholog of Sir2, SirT1, enhances cellular stress resistance and inhibits apoptosis, thereby promoting cell survival following cellular stresses. These cellular functions might contribute to an anti-aging effect. 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 might have important implications in both aging and cancer, making SirT1 activity a double-edged sword that requires tight regulation. However, the mode of SirT1 regulation is unclear. By affinity purification, we identified Deleted in Breast Cancer -1 (DBC1) as a SirT1-associated protein. The DBC1 gene localizes to human chromosome 8p21, a locus that is frequently deleted in breast cancers and the DBC1 transcripts are absent in 16% of breast cancer cell lines. Our preliminary results suggest that DBC1 is a negative regulator of SirT1. We hypothesize that DBC1 is a tumor suppressor that negatively regulates SirT1. Loss of DBC1 will result in hyperactivation of SirT1 and render cells resistant to cell death, thereby promoting tumorigenesis. In this proposal, we will map the regions that are responsible for the SirT1-DBC1 interaction at the molecular level. In addition, we will investigate how DBC1 affects SirT1 activity and function at the cellular level. Finally, we will generate DBC1 knockout mice and study the role of DBC1 in SirT1 regulation and tumor suppression at the organismal level. These studies will shed new light on the regulation of SirT1 and the potential role of DBC1 in suppressing breast cancer development.
The SirT1 enzyme is proposed to regulate aging process. In addition, high activity of SirT1 is linked to tumor growth. We want to understand the how SirT1 is regulated in the cell. We identified a protein called DBC1 (Deleted in Breast Cancer-1) that can inhibit SirT1. A region of human chromosome 8 containing the DBC1 gene is frequently deleted in breast cancers, and loss of DBC1 expression has been detected in some breast cancer cell lines. We hypothesize that DBC1 is a tumor suppressor that negatively regulates SirT1. In this study, we will examine how DBC1 regulates SirT1. In addition, to model human breast cancer development, we will delete the DBC1 gene in mice to test if loss of DBC1 would lead to tumor formation. These studies will shed new light on the regulation of SirT1 by DBC1 and the potential role DBC1 in suppressing breast cancer development.