Novel targets that are deregulated by loss of PTEN

由于 PTEN 缺失而解除管制的新靶标

• 批准号: 8919255
• 负责人: DEBORAH L. JOHNSON
• 金额: $ 29.36万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-06 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8919255
• 关键词: A Mouse; Acetyl-CoA Carboxylase; Affect; Age-Months; Apoptotic; Binding; Binding Proteins; Binding Sites; Biogenesis; Biological; Biological Assay; Biological Models; Cancer Biology; Cell Culture Techniques; Cell Line; Cells; ChIP-seq; Complex; DNA Polymerase II; DNA Polymerase III; Development; Disease; Enhancers; Enzymes; Event; Fatty Liver; Fatty-acid synthase; Gene Expression Process; Gene Targeting; Genes; Genetic Models; Genetic Transcription; Goals; Grant; Growth; Hepatic; Hepatocyte; Human; Human Development; Intracellular Accumulation of Lipids; Link; Lipids; Liver; Liver diseases; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Metabolic; Metabolism; Molecular; Molecular Models; Mouse Cell Line; Mus; Mutate; Nuclear; Obesity; Oncogenic; PI3K/AKT; PTEN gene; Pathology; Pathway interactions; Phosphorylation; Play; Primary carcinoma of the liver cells; Prostate; Prostatic Neoplasms; Protein Biosynthesis; Proteins; RNA; RNA Polymerase II; RNA Polymerase III; Recruitment Activity; Regulatory Element; Repression; Ribosomal RNA; Role; Sequence Analysis; Signal Pathway; Signal Transduction; Sterols; System; Testing; Transcription Factor TFIIIB; Transcription Repressor/Corepressor; Transfer RNA; Transgenic Model; Tumor Suppressor Proteins; cell growth; chromatin immunoprecipitation; gene induction; gene repression; genome-wide; glucose metabolism; lipid biosynthesis; lipid metabolism; metaplastic cell transformation; molecular modeling; mouse model; novel; prevent; promoter; tumor; tumorigenesis

DESCRIPTION (provided by applicant): A fundamental question in cancer biology is how metabolic changes drive the development of cancer. Although obesity has been recognized as a key factor in the development of human cancer, the underlying mechanisms that connect these two pathologies are not well understood. PTEN, a key tumor suppressor, regulates glucose and lipid metabolism. In our previous grant period we defined new classes of genes, transcribed by RNA polymerase III, which are targeted by PTEN and crucial for its function as a tumor suppressor. We also made a key discovery that loss of PTEN results in a substantial decrease in the expression of Maf1, a molecule that has proven, unexpectedly, to be a central negative regulator of transcription. PTEN regulates Maf1 expression by inhibiting activation of the PI3K signaling pathway. Our studies characterized mammalian Maf1 and showed that it directly represses select genes transcribed by RNA polymerases II and III that promote an oncogenic state. In addition, increased Maf1 expression suppresses cellular transformation. Importantly, our new results demonstrate that in cell culture, Maf1 negatively regulates lipid accumulation by repressing the expression of key enzymes necessary for lipid biosynthesis that are elevated in many human cancers. Together, these results support the ideas that Maf1 may be a critical target of PTEN, and that Maf1 is important both for its ability to regulate metabolism as well as function as a tumor suppressor. We therefore hypothesize that loss of PTEN, and resulting activation of PI3K/AKT, result in a decrease of Maf1, which alleviates the normal repression of genes involved in lipid biogenesis and growth control, leading to fatty liver disease and tumorigenesis. We plan to test this hypothesis in three aims using both molecular and biological models. Aim 1 will identify the specific PI3K/PTEN-dependent molecular signaling events that regulate Maf1 expression. Aim 2 will elucidate how Maf1 regulates fatty acid synthase and will identify other Maf1-regulated genes involved in lipid biosynthesis. In Aim 3, we will establish mouse models where Maf1 expression is increased in the livers of mice deficient in PTEN. A genetic model in which Pten is deleted in the liver has been described. These mice, which have reduced Maf1 levels in the liver, develop steatosis starting at one month and liver cancer at 9-12 months of age. Importantly, the development of fatty liver disease is required for tumor formation. This mouse model will allow us to determine whether restoring Maf1 amounts to livers that are deficient for Pten prevents or delays the onset of fatty liver disease and tumorigenesis. If successful, these studies will identify a novel role for Maf1 as a central coordinator of metabolic signals and will thus provide a new molecular mechanism for the long-known association between obesity and cancer.

描述（由申请人提供）：癌症生物学的一个基本问题是代谢变化如何驱动癌症的发展。尽管肥胖已被认为是人类癌症发展的关键因素，但连接这两种病理的潜在机制尚不清楚。 PTEN 是一种关键的肿瘤抑制因子，调节葡萄糖和脂质代谢。在我们之前的资助期间，我们定义了由 RNA 聚合酶 III 转录的新基因类别，这些基因是 PTEN 的靶标，对其作为肿瘤抑制因子的功能至关重要。我们还发现了一个关键的发现，即 PTEN 的缺失会导致 Maf1 表达的大幅下降，而 Maf1 已被意外地证明是转录的中央负调节因子。 PTEN 通过抑制 PI3K 信号通路的激活来调节 Maf1 的表达。我们的研究对哺乳动物 Maf1 进行了表征，并表明它直接抑制由 RNA 聚合酶 II 和 III 转录的、促进致癌状态的选定基因。此外，Maf1 表达增加会抑制细胞转化。重要的是，我们的新结果表明，在细胞培养中，Maf1 通过抑制脂质生物合成所需的关键酶的表达来负向调节脂质积累，而脂质生物合成所需的关键酶在许多人类癌症中升高。总之，这些结果支持这样的观点：Maf1 可能是 PTEN 的关键靶标，并且 Maf1 因其调节代谢的能力以及作为肿瘤抑制因子的功能而发挥重要作用。因此，我们假设 PTEN 的缺失以及由此产生的 PI3K/AKT 的激活会导致 Maf1 的减少，从而减轻参与脂质生物发生和生长控制的基因的正常抑制，从而导致脂肪肝疾病和肿瘤发生。我们计划使用分子和生物学模型在三个目标上测试这一假设。目标 1 将鉴定调节 Maf1 表达的特定 PI3K/PTEN 依赖性分子信号转导事件。目标 2 将阐明 Maf1 如何调节脂肪酸合酶，并将识别参与脂质生物合成的其他 Maf1 调节基因。在目标 3 中，我们将建立小鼠模型，其中缺乏 PTEN 的小鼠肝脏中 Maf1 表达增加。已经描述了肝脏中 Pten 被删除的遗传模型。这些小鼠肝脏中的 Maf1 水平降低，在 1 个月大时开始出现脂肪变性，并在 9-12 个月大时出现肝癌。重要的是，脂肪肝疾病的发展是肿瘤形成所必需的。该小鼠模型将使我们能够确定恢复 Maf1 是否相当于缺乏 Pten 的肝脏可以预防或延缓脂肪肝疾病和肿瘤发生的发生。如果成功，这些研究将确定 Maf1 作为代谢信号中央协调器的新作用，从而为长期以来已知的肥胖与癌症之间的关联提供新的分子机制。