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: 8248605
• 负责人: DEBORAH L. JOHNSON
• 金额: $ 30.58万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 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/8248605
• 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; Carcinoma; Cell Culture Techniques; Cell Line; Cells; 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; 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. PUBLIC HEALTH RELEVANCE: Our studies will continue to define novel and unexpected targets of the key tumor suppressor, PTEN. We will identify new mechanisms that control gene expression processes that are crucial for PTEN to negatively regulate lipid metabolism and tumorigenesis. Given the strong association between obesity and cancer, these studies will provide a new molecular mechanism that connects these two diseases and thereby substantially influence our understanding and treatment of these diseases.

描述(申请人提供)：癌症生物学中的一个基本问题是代谢变化如何驱动癌症的发展。虽然肥胖已被认为是人类癌症发展的关键因素，但将这两种病理联系起来的潜在机制尚不清楚。PTEN是一种关键的肿瘤抑制因子，调节糖脂代谢。在我们之前的资助期间，我们定义了新的基因类别，由RNA聚合酶III转录，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。我们还取得了一个关键发现，即PTEN的缺失会导致Maf1的表达大幅下降，Maf1是一个出人意料的分子，被证明是转录的中心负调控因子。PTEN通过抑制PI3K信号通路的激活来调节Maf1的表达。我们的研究描述了哺乳动物Maf1的特征，并表明它直接抑制由RNA聚合酶II和III转录的特定基因，这些基因促进了致癌状态。此外，Maf1表达的增加抑制了细胞转化。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的积累，而脂质生物合成在许多人类癌症中都是升高的。总之，这些结果支持这样的观点，即Maf1可能是PTEN的关键靶点，并且Maf1对其调节新陈代谢的能力以及作为肿瘤抑制因子的功能都是重要的。因此，我们假设PTEN的缺失和由此导致的PI3K/AKT的激活导致Maf1的减少，从而减轻了参与脂质生物发生和生长控制的基因的正常抑制，导致脂肪肝和肿瘤的发生。我们计划使用分子和生物模型从三个方面检验这一假说。目的1鉴定调控Maf1表达的依赖于PI3K/PTEN的特异性分子信号事件。目的2将阐明Maf1是如何调节脂肪酸合成酶的，并将确定其他参与脂质生物合成的Maf1调节基因。在目标3中，我们将建立PTEN缺陷小鼠肝脏中Maf1表达增加的小鼠模型。已经描述了一种在肝脏中缺失Pten的遗传模型。这些小鼠降低了肝脏中Maf1的水平，在一个月大时开始发生脂肪变性，在9-12个月大时患上肝癌。重要的是，脂肪肝的发展是肿瘤形成的必要条件。这个小鼠模型将使我们能够确定恢复Maf1相当于缺乏Pten的肝脏是否可以预防或推迟脂肪性肝病和肿瘤的发生。如果成功，这些研究将确定Maf1作为代谢信号的中心协调者的新角色，从而为长期以来已知的肥胖和癌症之间的联系提供新的分子机制。 公共卫生相关性：我们的研究将继续确定关键的肿瘤抑制因子PTEN的新的和意想不到的靶点。我们将确定控制基因表达过程的新机制，这些机制对PTEN负向调节脂质代谢和肿瘤发生至关重要。鉴于肥胖和癌症之间的密切联系，这些研究将提供一种新的分子机制，将这两种疾病联系起来，从而极大地影响我们对这些疾病的理解和治疗。