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

乳腺癌 1 缺失 (DBC1) 对 SirT1 的调控

• 批准号: 8011471
• 负责人: Zhenkun Lou
• 金额: $ 30.41万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011471
• 关键词: 8p21; Affect; Affinity Chromatography; Aging; Apoptosis; Apoptotic; BRCA1 gene; Biological Process; Cancer cell line; Carcinogens; Cell Survival; Cell physiology; Cellular Stress Response; DNA Damage; Deacetylase; Down-Regulation; Energy Metabolism; Health; Inhibition of Apoptosis; KIAA1967 gene; Knockout Mice; Light; Link; Longevity; Malignant Neoplasms; Malignant neoplasm of lung; Mammalian Cell; Mass Spectrum Analysis; Molecular; Mus; Orthologous Gene; Peroxisome Proliferator-Activated Receptors; Phosphorylation; Phosphorylation Site; Physiological; Proteins; Regulation; Role; Signal Pathway; Yeasts; age effect; anti aging; base; biological adaptation to stress; cell growth; insight; malignant breast neoplasm; neoplastic cell; response; transcription factor; tumor; tumorigenesis

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.

描述（由申请人提供）： SirT 1是酵母Sir 2在哺乳动物中的同源基因，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，SirT 1活性对于肿瘤细胞生长和存活也是重要的，这可能是由于SirT 1的抗凋亡作用。因此，SirT 1在衰老和癌症中都有重要意义，使得SirT 1活性成为一把双刃剑，需要严格的调控。然而，SirT 1的调控尚不清楚。为了了解SirT 1的调控，我们着手鉴定SirT 1相关蛋白。通过串联亲和纯化和质谱分析，我们已经确定在乳腺癌中删除的-1（DBC 1）作为SirT 1相关蛋白。DBC 1基因定位于乳腺癌中经常缺失的区域（8 p21）;在一些乳腺癌和肺癌细胞系中检测到DBC 1表达缺失。然而，DBC 1的损失和肿瘤发生之间的因果关系尚未建立。DBC 1蛋白的细胞功能也不清楚。我们的初步结果表明，DBC 1直接与SirT 1相互作用，抑制SirT 1的活性。DBC 1的下调增强了SirT 1依赖的对DNA损伤的细胞凋亡的抑制。此外，DBC 1的缺失在致癌物存在下促进肿瘤发生。基于这些观察结果，我们假设DBC 1负调控SirT 1，从而影响DNA损伤反应，衰老和肿瘤发生。在此基础上，我们提出以下具体目标：1.研究DBC 1的SirT 1依赖性和SirT 1非依赖性功能。2.研究DNA损伤后SirT 1-DBC 1相互作用的调节。3.利用DBC 1基因敲除小鼠探讨DBC 1在衰老和肿瘤发生中的生理作用。这些研究的结果不仅将为SirT 1的调控提供新的线索，还将为衰老和癌症的分子机制提供重要的见解。公共卫生相关性：蛋白质脱乙酰酶SirT 1与衰老和癌症有关。然而，SirT 1的调控尚不清楚。我们将研究DBC 1对SirT 1的调控，这将为衰老和癌症的分子机制提供重要的见解。