Regulation of SirT1 by Deleted in Breast Cancer 1 (DBC1)

描述（由申请人提供）：SirT1，酵母Sir2的哺乳动物同源物，调节哺乳动物细胞中的多种细胞过程，如细胞应激反应和能量代谢，有助于可能的抗衰老作用。另一方面，SirT1的活性对肿瘤细胞的生长和存活也很重要，这可能是由于SirT1的抗凋亡作用。因此，SirT1在衰老和癌症中都具有重要意义，这使得SirT1的活性成为一把双刃剑，需要严格调控。然而，SirT1的调控尚不清楚。为了了解SirT1的调控，我们开始鉴定SirT1相关蛋白。通过串联亲和纯化和质谱分析，我们已经确定了乳腺癌中删除的1 （DBC1）是SirT1相关蛋白。DBC1基因定位于乳腺癌中经常缺失的一个区域（8p21）；在一些乳腺癌和肺癌细胞系中检测到DBC1表达缺失。然而，DBC1缺失与肿瘤发生之间的因果关系尚未确定。DBC1蛋白的细胞功能也不清楚。我们的初步结果表明DBC1直接与SirT1相互作用并抑制SirT1活性。DBC1的下调增强了sirt1依赖性的细胞凋亡抑制，以响应DNA损伤。此外，在致癌物存在的情况下，DBC1的缺失会促进肿瘤的发生。基于这些观察，我们假设DBC1负调控SirT1，从而影响DNA损伤反应、衰老和肿瘤发生。在以往观察的基础上，我们提出以下具体目标：研究sirt1依赖性和非依赖性DBC1的功能。2. 研究DNA损伤后SirT1-DBC1相互作用的调控。3. 利用DBC1敲除小鼠，探讨DBC1在衰老和肿瘤发生中的生理作用。这些研究结果不仅为SirT1的调控提供了新的思路，而且为衰老和癌症的分子机制提供了重要的见解。公共卫生相关性：蛋白质去乙酰化酶SirT1与衰老和癌症有关。然而，SirT1的调控尚不清楚。我们将研究DBC1对SirT1的调控，这将为了解衰老和癌症的分子机制提供重要的见解。

DESCRIPTION (provided by applicant): 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.