Role of NIAM, A Putative Cancer Gene, in Chromosomal Instability and Gliobastoma

描述(由申请人提供)：不受控制的细胞增殖、p53肿瘤抑制信号改变和染色体不稳定(CIN)是肿瘤发生的标志性特征。我的论文实验室发现了一种新的p53信号激活剂，称为NIAM(ARF和MDM2的核相互作用)。NIAM是一种新的预防CIN和抑制细胞增殖的蛋白质，其mRNA在人类多形性胶质母细胞瘤(GBM)等癌症中表达下调。NIAM与ARF、MDM2和P53有功能联系，但其抑制增殖和CIN的作用不依赖于这三个因素。因此，NIAM在多个抗癌途径中发挥作用。NIAM如何维持染色体的稳定性及其在癌症中的意义尚不清楚。CIN的一个主要原因是DNA损伤修复错误。我们的初步数据显示，NiAM是一种染色质相关蛋白，定位于DNA修复焦点，增强DNA损伤反应，并与组蛋白乙酰转移酶Tip60结合。像NIAM一样，Tip60结合染色质，激活P53，并与ARF和MDM2功能相互作用。Tip60也可以独立于ARF-MDM2-P53发挥作用，激活DNA损伤检查点，促进DNA修复，维持染色体稳定。基于这些观察，我推测NiAM是一种肿瘤抑制因子，它通过与Tip60相互作用和/或促进DNA修复来抑制CIN和癌症。提出了三个目标来验证这一假说，并使用互补的分子、生物学和基因组方法来定义NIAM的生物学功能。目的1：确定NIAM是否通过染色质结合和DNA损伤修复来维持染色体的稳定性。目的2：明确NIAM-Tip60结合的分子基础和意义。目的3：确定NIAM缺失、CIN和癌症之间是否存在联系。这些研究是新颖而有意义的，因为它们将确定NIAM(一种假定的肿瘤抑制因子)维持染色体稳定从而保持基因组完整性的机制。实验(目标3)还探讨了在最具侵袭性和最常见的成人脑癌类型--GBM中，NiAM表达和CIN的变化的意义。这项工作可能会改进GBM的诊断和治疗，GBM是一种致命的癌症，目前仍缺乏有效的治疗方法。重要的是，这是一个多学科的论文项目，将极大地提高我在分子细胞生物学方面的技能，并教会我如何研究癌症的机制、生物学和基因组学。我的最终目标是成为一名研究儿科癌症的独立内科科学家。我感到兴奋的是，这次培训经验将有效地为我在翻译癌症研究领域的职业生涯做好准备。 公共卫生相关性：多形性胶质母细胞瘤(GBM)是一种与严重的染色体不稳定(CIN)相关的侵袭性癌症，由于缺乏预后生物标志物和有效的治疗方法，它具有很高的死亡率。本项目研究了一种新的潜在的GBM生物标志物如何控制CIN和神经胶质瘤的发生。这些发现有望促进我们对GBM分子基础的理解，并可能改善这种毁灭性疾病患者的检测和治疗。

DESCRIPTION (provided by applicant): Uncontrolled cellular proliferation, altered p53 tumor suppressor signaling, and chromosomal instability (CIN) are signature features of tumorigenesis. My thesis laboratory discovered a new activator of p53 signaling called NIAM (Nuclear Interactor of ARF and Mdm2). NIAM is a novel protein that prevents CIN and inhibits cell proliferation, and its mRNA is reduced in human cancers such as glioblastoma multiforme (GBM). NIAM has functional connections with ARF, Mdm2 and p53 yet it can suppress proliferation and CIN independent of all three factors. Thus, NIAM functions in multiple anti-cancer pathways. How NIAM maintains chromosome stability and its significance in cancer are unknown. A major cause of CIN is faulty DNA damage repair. Our preliminary data reveal NIAM is a chromatin-associated protein that localizes to DNA repair foci, enhances the DNA damage response, and binds the histone acetyltransferase Tip60. Like NIAM, Tip60 binds chromatin, activates p53 and interacts functionally with ARF and Mdm2. Tip60 can also act independently of ARF-Mdm2- p53 to activate DNA damage checkpoints, promote DNA repair, and maintain chromosome stability. Based on these observations, I hypothesize that NIAM is a tumor suppressor that inhibits CIN and cancer through its interaction with Tip60 and/or promoting DNA repair. Three aims are proposed to test that hypothesis and define the biological function of NIAM using complementary molecular, biological and genomic approaches. Aim 1: Determine if NIAM maintains chromosomal stability through chromatin association and DNA damage repair. Aim 2: Define the molecular basis and significance of NIAM-Tip60 association. Aim 3: Determine if there is a link between NIAM loss, CIN and cancer. These studies are novel and significant because they will define the mechanisms by which NIAM, a putative tumor suppressor, maintains chromosomal stability and thus genomic integrity. Experiments (Aim 3) also explore the significance of altered NIAM expression and CIN in GBM, the most aggressive and prevalent type of adult brain cancer. This work may improve the diagnosis and treatment of GBM, a deadly cancer which still lack effective therapies. Importantly, this is a multi-disciplinar thesis project that will greatly advance my skills in molecular cell biology and teach me how to study the mechanisms, biology and genomics of cancer. My ultimate goal is to become an independent physician scientist studying pediatric cancers. I am excited that this training experience will effectively prepare me for such a career in translational cancer research. PUBLIC HEALTH RELEVANCE: Gliobastoma multiforme (GBM) is an aggressive cancer associated with significant chromosomal instability (CIN), and it has high mortality due to the lack of prognostic biomarkers and effective treatments. This project examines how a new potential biomarker of GBM functions to control CIN and gliomagenesis. Findings are expected to advance our understanding of the molecular basis of GBM and possibly improve detection and treatment of patients with this devastating disease.