Novel targets that are deregulated by loss of PTEN

描述（由申请人提供）：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一个关键因素，但连接这两种病理的潜在机制尚未得到很好的理解。PTEN是一种重要的肿瘤抑制因子，调节糖和脂质代谢。在我们之前的资助期间，我们定义了由RNA聚合酶III转录的新型基因，这些基因被PTEN靶向，并且对于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的缺失导致Maf 1表达的大幅下降，Maf 1是一种已被证明是转录的中心负调节因子的分子。PTEN通过抑制PI 3 K信号通路的激活来调节Maf 1的表达。我们的研究特征哺乳动物Maf 1，并表明它直接抑制选择基因转录的RNA聚合酶II和III，促进致癌状态。此外，Maf 1表达增加抑制细胞转化。重要的是，我们的新结果表明，在细胞培养中，Maf 1通过抑制脂质生物合成所必需的关键酶的表达来负调节脂质积累，这些酶在许多人类癌症中升高。总之，这些结果支持Maf 1可能是PTEN的关键靶点的想法，并且Maf 1对于其调节代谢的能力以及作为肿瘤抑制剂的功能都很重要。因此，我们假设，PTEN的丢失，并导致PI 3 K/AKT的激活，导致Maf 1的减少，这加剧了参与脂质生物合成和生长控制的基因的正常抑制，导致脂肪肝疾病和肿瘤发生。我们计划使用分子和生物模型在三个目标中测试这一假设。目的1将确定特定的PI 3 K/PTEN依赖的分子信号传导事件，调节Maf 1的表达。目的2将阐明Maf 1如何调节脂肪酸合成酶，并将确定其他Maf 1调节的基因参与脂质生物合成。在目标3中，我们将建立小鼠模型，其中Maf 1表达在PTEN缺陷小鼠的肝脏中增加。已经描述了Pten在肝脏中缺失的遗传模型。这些小鼠肝脏中Maf 1水平降低，从一个月开始发生脂肪变性，在9-12个月大时发生肝癌。重要的是，脂肪肝疾病的发展是肿瘤形成所必需的。这种小鼠模型将使我们能够确定恢复Maf 1是否相当于Pten缺乏的肝脏预防或延迟脂肪肝疾病和肿瘤发生的发生。如果成功，这些研究将确定Maf 1作为代谢信号中心协调者的新作用，从而为肥胖和癌症之间长期已知的关联提供新的分子机制。 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，这些基因表达过程对PTEN负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，从而大大影响我们对这些疾病的理解和治疗。

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.