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: 8701256
• 负责人: ANTHONY John CAPOBIANCO
• 金额: $ 30.8万
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701256
• 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，包括淋巴系统肿瘤、胰腺肿瘤、乳腺癌和中枢神经系统肿瘤。这种转化活性是Notch的固有属性，它通过转录调控复合体介导其影响。然而，关于导致Notch转录激活复合体形成的分子事件，仍然缺乏大量的知识。伽马分泌酶抑制剂(GSI)是唯一针对Notch的药物，正在临床试验中进行疗效测试。然而，异常表达的Notch胞内域(NICD)对GSI治疗没有反应，因此在Notch通路中寻找适合作为药物靶点的新元件成为当务之急。为此，我们在Notch转录激活复合体中寻找新的成分，并鉴定出一种新的Notch相关蛋白，我们将其命名为Notch激活复合体激酶(NACK)。NACK作为Notch转录活性的辅助激活因子，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认Nack是Notch转录复合体的一个新成员，并可能是抑制Notch途径的靶点。这一提议的基本假设是NAK是一个转录辅助激活因子，与肿瘤的发生有关。我们的目标是确定调控NACK功能的分子机制，确定其在肿瘤发生中的作用，并探讨NACK作为肿瘤生物标记物和抗癌治疗的潜在药理靶点的前景。这项建议的具体目的是：1)研究NACK与Notch转录调控复合体相互作用的分子基础；2)利用条件性NACK-KO小鼠研究NACK在体内的功能；3)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的功能，以便为癌症治疗的合理设计做出贡献