The ARF Tumor Suppressor

ARF肿瘤抑制剂

• 批准号: 8011341
• 负责人: Maureen E. Murphy
• 金额: $ 35.12万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2011-11-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011341
• 关键词: 1-Phosphatidylinositol 3-Kinase; 3-methyladenine; ANXA2 gene; Abbreviations; Address; Amino Acids; Antineoplastic Agents; Autophagocytosis; Binding; Binding Proteins; Biochemistry; Breast Carcinoma; Buffers; Burkitt Lymphoma; CDKN2A gene; Calcium; Catabolic Process; Cell Line; Cell Survival; Cells; Chemicals; Chloroquine; Data; Development; Digestion; Disaccharides; E2F1 gene; Foundations; Genes; Genetic; Glucose; Goals; Growth; Health; Human; Lipids; Lymphoma; Lysosomes; MDM2 gene; Malaria; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Membrane; Metabolic stress; Mitochondria; Mitochondrial Proteins; Mus; Mutate; Mutation; Nutrient; Oncogenic; Organelles; Ovarian Carcinoma; Pathway interactions; Pharmaceutical Preparations; Phosphatidylinositide 3-Kinase Inhibitor; Phospholipids; Phosphotransferases; Play; Process; Proteins; Research; Rheumatoid Arthritis; Role; Signal Transduction; Sodium Chloride; Solutions; Starvation; Stress; Terminology; Testing; Trehalose; Tumor Suppressor Genes; Tumor Suppressor Proteins; Up-Regulation; c-myc Genes; cancer cell; cancer therapy; combat; deprivation; gene repression; human FRAP1 protein; in vivo; inhibitor/antagonist; mutant; neoplastic cell; novel; nucleophosmin; overexpression; p19ARF; public health relevance; response; sarcoma; small molecule; tumor; tumorigenesis; ubiquitin ligase

DESCRIPTION (provided by applicant): The ARF tumor suppressor protein is encoded by the Ink4a/ARF gene, which is the second most frequently mutated genetic locus in human cancer. To date the majority of research on ARF has focused on its tumor suppressor functions. This proposal focuses instead on a novel survival function for ARF that we have recently uncovered, and that exists for a subset of tumors with mutant/null p53. We show that ARF plays an integral role in starvation-induced autophagy. Autophagy is a self-catabolic process that promotes the survival of cells exposed to nutrient deprivation. Because tumor cells exist under uniquely metabolically-stressed conditions, many rely heavily on this pathway in order to subsist. Consistent with this fact, autophagy inhibitors have shown promise as anti-cancer agents. We show that ARF protein is markedly up-regulated in response to nutrient deprivation. We show that silencing ARF impedes autophagy and decreases the survival of nutrient-deprived cells. Finally, we show that silencing ARF in lymphomas impairs autophagy and survival, and actually impedes the development of these tumors. The central hypothesis of this proposal is that ARF-mediated autophagy is utilized by a subset of tumors with mutant p53 to allow them to survive episodes of metabolic stress. We contend that the requirement for the survival function of autophagy is an 'Achilles heel' for tumors. We need to better understand this pathway in order to exploit it for cancer therapy. In proposed research we will elucidate the mechanism(s) whereby ARF induces autophagy. We will determine how nutrient deprivation leads to increased ARF protein levels. We have found that ARF expression is beneficial for some tumors (lymphoma) but not others (sarcoma); we will define the subset of tumors that are benefited by ARF-mediated autophagy. We will determine whether critical mediators of autophagy, such as ARF and Beclin1, dictate tumor response to small molecules that modulate this process, such as chloroquine (inhibits autophagy), and trehalose (induces autophagy). Finally we will elucidate the mechanism of transcriptional repression of the ARF locus by p53, as this leads to ARF up-regulation in p53-mutant tumors. The combined data will serve as a necessary foundation for exploiting the pathway of autophagy for cancer therapy. PUBLIC HEALTH RELEVANCE: The ARF gene is encoded by the Ink4a/ARF locus, which is the second most commonly mutated genetic locus in human cancer; up to 50% of human tumors contain mutations in Ink4a/ARF. This fact argues that research aimed at understanding the basic function of ARF in human cancer is warranted. We show that ARF controls a key survival pathway for tumor cells. We believe that the requirement for ARF and autophagy may be an Achilles Heel for tumor cells. This research is aimed at understanding this pathway, and at finding ways to manipulate this pathway to combat cancer.

描述（由申请人提供）：ARF肿瘤抑制蛋白由Ink4a/ARF基因编码，该基因是人类癌症中第二常见突变的基因位点。迄今为止，ARF 的大部分研究都集中在其肿瘤抑制功能上。该提案的重点是我们最近发现的一种新的 ARF 生存函数，该函数存在于 p53 突变/无效的肿瘤子集中。我们证明 ARF 在饥饿诱导的自噬中发挥着不可或缺的作用。自噬是一种自我分解代谢过程，可促进营养匮乏的细胞存活。由于肿瘤细胞存在于独特的代谢应激条件下，因此许多肿瘤细胞严重依赖该途径才能生存。与这一事实一致，自噬抑制剂已显示出作为抗癌药物的前景。我们发现 ARF 蛋白因营养缺乏而显着上调。我们发现沉默 ARF 会阻碍自噬并降低营养缺乏细胞的存活率。最后，我们发现在淋巴瘤中沉默 ARF 会损害自噬和存活，并且实际上阻碍了这些肿瘤的发展。该提议的中心假设是，具有突变 p53 的肿瘤子集利用 ARF 介导的自噬，使它们能够在代谢应激发作时存活下来。 我们认为，自噬生存功能的要求是肿瘤的“致命弱点”。我们需要更好地了解这一途径，以便将其用于癌症治疗。在拟议的研究中，我们将阐明 ARF 诱导自噬的机制。我们将确定营养缺乏如何导致 ARF 蛋白水平增加。我们发现 ARF 表达对某些肿瘤（淋巴瘤）有益，但对其他肿瘤（肉瘤）则无益；我们将定义受益于 ARF 介导的自噬的肿瘤子集。我们将确定自噬的关键介质（例如 ARF 和 Beclin1）是否决定肿瘤对调节该过程的小分子（例如氯喹（抑制自噬）和海藻糖（诱导自噬））的反应。最后，我们将阐明 p53 对 ARF 位点转录抑制的机制，因为这会导致 p53 突变肿瘤中 ARF 上调。合并后的数据将成为利用自噬途径进行癌症治疗的必要基础。 公共健康相关性：ARF 基因由 Ink4a/ARF 位点编码，该位点是人类癌症中第二个最常见的突变基因位点；高达 50% 的人类肿瘤含有 Ink4a/ARF 突变。这一事实表明，旨在了解 ARF 在人类癌症中基本功能的研究是必要的。我们证明 ARF 控制肿瘤细胞的关键生存途径。我们认为，ARF 和自噬的需求可能是肿瘤细胞的致命弱点。这项研究旨在了解这一途径，并寻找操纵该途径来对抗癌症的方法。