Characterization of NACK, an essential coactivator of Notch, in tumorigenesis

NACK（Notch 的重要共激活因子）在肿瘤发生中的表征

• 批准号: 8895283
• 负责人: ANTHONY John CAPOBIANCO
• 金额: $ 31.75万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8895283
• 关键词: Affect; Binding; Biological Markers; Breast; CCL2 gene; Cell Survival; Cells; Clinical Trials; Complex; Development; Drug Targeting; Embryo; Event; Figs - dietary; Gene Family; Goals; Human; Indium; Knock-out; Knockout Mice; Knowledge; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Monoubiquitination; Mus; Normal tissue morphology; Organ; Organogenesis; Pancreas; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Property; Proteins; Role; Solid Neoplasm; Specificity; System; Testing; Therapeutic; Tissues; Toxic effect; Transcriptional Activation; base; cancer cell; cancer therapy; cell transformation; design; efficacy testing; gamma secretase; in vivo; inhibitor/antagonist; lymphoid neoplasm; member; metaplastic cell transformation; notch protein; novel; paralogous gene; tumor; tumor initiation; tumorigenesis

DESCRIPTION (provided by applicant): Substantial evidence has demonstrated a role for the Notch gene family in multiple human cancers, including neoplasms of the lymphoid system, pancreas, breast and CNS. This transforming activity is an intrinsic property of Notch, which mediates its effects through a transcriptional regulatory complex. However, there remains a significant lack of knowledge with respect to the molecular events leading to the formation of the Notch transcriptional activation complex. Gamma secretase inhibitors (GSIs) are the only drugs targeting Notch that are being tested for efficacy in clinical trials. However, aberrantly expresse Notch intracellular domain (NICD) does not respond to GSI treatment, turning into a high priority the search of new elements in the notch pathway suitable to be pharmacologically targeted. With this purpose, we have searched for new components in the Notch transcriptional activation complex and have identified a novel Notch-associated protein, we termed Notch Activation Complex Kinase (NACK). NACK functions as a co-activator of Notch transcriptional activity and it is expressed in human tumors but not in the adjacent normal tissue. Furthermore, NACK is required for Notch-driven cell transformation. Our preliminary results convincingly identify NACK as a new member of the Notch transcriptional complex and a putative target to inhibit Notch pathway. The underlying hypothesis of this proposal is that NAK is a transcriptional co-activator implicated in tumorigenesis. Our goal is to characterize th molecular mechanisms regulating NACK function, to determine its role in tumorigenesis and to investigate the prospect of using NACK as a tumor biomarker and a putative pharmacological target in anti-cancer therapies. The specific aims of this proposal are: i) Characterize the molecular basis of the interaction between NACK and the Notch transcriptional regulatory complex~ ii) Characterize NACK function in vivo using a conditional NACK-KO mouse~ and iii) Determine the role of NACK in Notch-driven tumorigenesis. The long-range goal for these studies is to obtain a comprehensive understanding of NACK function in order to contribute to the rational design of cancer therapeutics

描述（由申请人提供）：大量证据表明 Notch 基因家族在多种人类癌症中发挥作用，包括淋巴系统、胰腺、乳腺癌和中枢神经系统肿瘤。 这种转化活性是 Notch 的固有特性，它通过转录调节复合物介导其作用。然而，对于导致Notch转录激活复合物形成的分子事件仍然严重缺乏了解。 γ 分泌酶抑制剂 (GSI) 是唯一正在临床试验中测试疗效的针对 Notch 的药物。然而，异常表达的Notch胞内结构域（NICD）对GSI治疗没有反应，因此在Notch通路中寻找适合药理学靶向的新元件成为当务之急。为此，我们在Notch转录激活复合物中寻找新的成分，并鉴定了一种新的Notch相关蛋白，我们将其命名为Notch激活复合物激酶（NACK）。 NACK 是 Notch 转录活性的共激活因子，在人类肿瘤中表达，但在邻近的正常组织中不表达。此外，Notch 驱动的细胞转化需要 NACK。我们的初步结果令人信服地确定 NACK 是 Notch 转录复合物的新成员，也是抑制 Notch 通路的假定靶点。 该提议的基本假设是 NAK 是一种与肿瘤发生有关的转录共激活因子。我们的目标是表征调节 NACK 功能的分子机制，确定其在肿瘤发生中的作用，并研究使用 NACK 作为肿瘤生物标志物和抗癌治疗中推定药理学靶点的前景。该提案的具体目标是：i) 表征 NACK 与 Notch 转录调节复合物之间相互作用的分子基础~ii) 使用条件 NACK-KO 小鼠表征 NACK 体内功能~以及 iii) 确定 NACK 在 Notch 驱动的肿瘤发生中的作用。 这些研究的长期目标是全面了解 NACK 功能，以便为癌症治疗的合理设计做出贡献