Growth Inhibition by the ARF Tumor Suppressor

ARF 肿瘤抑制剂的生长抑制

• 批准号: 7893692
• 负责人: DAWN E QUELLE
• 金额: $ 26.59万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893692
• 关键词: Biochemical; Biological; Cancer Model; Cancer cell line; Cell Proliferation; DNA damage checkpoint; Development; Diagnosis; Funding; Genes; Genome Stability; Growth; Human; Link; Malignant Neoplasms; Mediating; Molecular; Mus; Nuclear; Oncogenes; Pathway interactions; Primary Neoplasm; Proteins; Public Health; RNA Interference; Research; Role; Signal Pathway; Signal Transduction; TP53 gene; Testing; Tumor Suppression; Tumor Suppressor Proteins; Work; anticancer activity; base; cancer cell; carcinogenesis; improved; mouse model; novel; prevent; protein protein interaction; tumor; tumorigenesis

DESCRIPTION (provided by applicant): INK4a/ARF encodes the ARF tumor suppressor protein and is the second most frequently inactivated gene in human cancers. ARF prevents oncogene-mediated transformation through protein-protein interactions in partially defined p53-dependent and p53-independent pathways. Numerous ARF-associated proteins have been identified but few besides the p53 antagonist, Mdm2, have a clearly defined role in ARF-mediated tumor suppression. Based on work from the previously funded project, we identified and characterized two novel ARF interacting proteins and showed they participate in ARF signaling. Parf (Partner of ARF) is required for ARF's p53-independent growth suppressive activity, whereas NIAM (Nuclear Interactor of ARF and Mdm2) activates p53 and collaborates with ARF to inhibit cell proliferation. Both proteins also act independent of ARF and p53 to maintain genomic stability, regulate DNA damage checkpoints, and suppress cancer cell proliferation, suggesting they have anticancer activities that intersect with ARF and other antiproliferative pathways. However, the underlying mechanisms by which Parf and NIAM regulate ARF signaling, genomic stability and cell proliferation are poorly understood. The specific objective of this research is to define the mechanistic and biological roles of these novel ARF interacting proteins in ARF signaling and carcinogenesis. Aim 1 will establish how NIAM enhances ARF signaling and its role in tumorigenesis. Aim 2 will define how Parf contributes to ARF signaling and tumor suppression. Molecular and biochemical approaches, as well as unique mouse models of cancer, will be utilized. These studies will advance our fundamental understanding of how the ARF tumor suppressor and its associated proteins prevent cancer. This is highly relevant to public health because loss of ARF figures prominently in the development of nearly all types of human tumors and we cannot effectively battle cancer until we know its molecular basis. This work is expected to identify new targets for anticancer strategies and new paradigms used by tumor suppressors to prevent tumorigenesis, and as such, it should improve our ability to diagnose, treat and ultimately prevent human cancer.

描述（由申请人提供）：INK4a/ARF 编码 ARF 肿瘤抑制蛋白，是人类癌症中第二常见失活的基因。 ARF 通过部分定义的 p53 依赖性和 p53 独立途径中的蛋白质-蛋白质相互作用来防止癌基因介导的转化。已鉴定出许多 ARF 相关蛋白，但除了 p53 拮抗剂 Mdm2 之外，很少有蛋白在 ARF 介导的肿瘤抑制中具有明确的作用。基于之前资助的项目的工作，我们鉴定并表征了两种新型 ARF 相互作用蛋白，并表明它们参与 ARF 信号传导。 Parf（ARF 的伙伴）是 ARF 独立于 p53 的生长抑制活性所必需的，而 NIAM（ARF 和 Mdm2 的核相互作用因子）则激活 p53 并与 ARF 协同抑制细胞增殖。这两种蛋白的作用也独立于 ARF 和 p53，以维持基因组稳定性、调节 DNA 损伤检查点并抑制癌细胞增殖，表明它们具有与 ARF 和其他抗增殖途径交叉的抗癌活性。然而，人们对 Parf 和 NIAM 调节 ARF 信号、基因组稳定性和细胞增殖的潜在机制知之甚少。本研究的具体目标是确定这些新型 ARF 相互作用蛋白在 ARF 信号传导和致癌作用中的机制和生物学作用。目标 1 将确定 NIAM 如何增强 ARF 信号传导及其在肿瘤发生中的作用。目标 2 将定义 Parf 如何促进 ARF 信号传导和肿瘤抑制。将利用分子和生化方法以及独特的小鼠癌症模型。 这些研究将增进我们对 ARF 肿瘤抑制因子及其相关蛋白如何预防癌症的基本了解。这与公共健康高度相关，因为 ARF 的丧失在几乎所有类型的人类肿瘤的发展中都起着重要作用，并且在我们了解其分子基础之前，我们无法有效地对抗癌症。这项工作有望确定抗癌策略的新靶点和肿瘤抑制因子用于预防肿瘤发生的新范例，因此，它应该提高我们诊断、治疗和最终预防人类癌症的能力。