Novel Mechanisms of PTEN Gene Regulation

PTEN基因调控的新机制

• 批准号: 7175421
• 负责人: Vivek M Rangnekar
• 金额: $ 28.63万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-05 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7175421
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Alpha 1 Casein Kinase 1; Apoptosis; Apoptotic; Cell Survival; Chromosome Deletion; Chromosomes; Chromosomes, Human, Pair 10; Clinical; DNA Methylation; Development; Down-Regulation; EP300 gene; Epigenetic Process; Gene Expression; Gene Expression Regulation; Genes; Homologous Gene; Human; Inhibition of Apoptosis; Intervention; Ionizing radiation; Lead; Loss of Heterozygosity; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of thyroid; Mutation; NF-kappa B; Non-Small-Cell Lung Carcinoma; Oncogenic; PTEN gene; Pathway interactions; Role; Signal Pathway; Thyroid carcinoma; Transcriptional Activation; Tumor Suppressor Genes; Up-Regulation; chemotherapeutic agent; gene function; novel; promoter; radiation resistance; ras Oncogene; response; tensin; transcription factor; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The pro-apoptotic tumor suppressor gene PTEN (Phospatase and Tensin Homologue deleted from Chromosome 10) is a negative regulator of the PI-3 kinase/Akt dependent cell survival pathway. PTEN is located on chromosome 10q23 within a region that shows loss of heterozygosity in many human cancers, and PTEN gene function is lost in diverse cancers either by mutation of PTEN or deletion of chromosome 10q23. However, in several cancers such as non-small cell lung cancer and thyroid cancer, the PTEN gene is intact and wild type, but its expression is diminished. As haplo-insufficiency of PTEN is associated with tumorigenesis, understanding the mechanism(s) involved in epigenetic down-regulation of PTEN is of both clinical and fundamental significance. Recent studies have shown that the PTEN pseudo-gene but not wild type PTEN gene is methylated, indicating that DNA methylation is not a potential mechanism for silencing of the PTEN promoter leading to diminished PTEN gene expression. Our preliminary studies indicated that the anti-apoptotic transcriptional regulator NF-kappaB and oncogenic Ras, which are over-expressed and activated in lung cancer, down-regulate the expression of PTEN. Interestingly, oncogenic Ras up-regulates the expression of the transcription factor Egr-1, which by itself suppresses PTEN gene expression. The studies proposed here will address the mechanisms for down-regulation of PTEN gene expression that are functionally relevant; i.e., they result in elevated phospho-Akt levels and anti-apoptosis. We will determine the mechanisms of suppression of PTEN gene expression by NF-kappaB (Aim 1), and by oncogenic Ras (Aim 2) that confer apoptosis inhibition, tumor progression and chemo- or radiation-resistance. Because these studies will elucidate novel mechanisms of PTEN tumor suppressor gene regulation by pro-survival and oncogenic factors most commonly encountered in lung cancer, the findings may lead to the development of intervention strategies that can ablate the NF-kappaB or activated Ras-inducible anti-apoptotic pathways and thereby restore expression and the pro-apoptotic potential of PTEN.

描述（由申请人提供）：促凋亡肿瘤抑制基因 PTEN（从染色体 10 删除的磷酸酶和张力蛋白同源物）是 PI-3 激酶/Akt 依赖性细胞存活途径的负调节因子。 PTEN 位于染色体 10q23 上的一个区域内，该区域在许多人类癌症中显示杂合性丧失，并且 PTEN 基因功能在多种癌症中通过 PTEN 突变或染色体 10q23 缺失而丧失。然而，在非小细胞肺癌和甲状腺癌等多种癌症中，PTEN基因是完整的野生型，但其表达量有所减少。由于 PTEN 单倍体不足与肿瘤发生相关，因此了解 PTEN 表观遗传下调所涉及的机制具有临床和基础意义。最近的研究表明，PTEN 假基因而非野生型 PTEN 基因被甲基化，这表明 DNA 甲基化不是 PTEN 启动子沉默导致 PTEN 基因表达减少的潜在机制。我们的初步研究表明，在肺癌中过度表达和激活的抗凋亡转录调节因子NF-kappaB和致癌Ras会下调PTEN的表达。有趣的是，致癌 Ras 上调转录因子 Egr-1 的表达，而 Egr-1 本身会抑制 PTEN 基因的表达。 这里提出的研究将解决功能相关的 PTEN 基因表达下调机制；即，它们导致磷酸 Akt 水平升高并抗凋亡。我们将确定 NF-kappaB（目标 1）和致癌 Ras（目标 2）抑制 PTEN 基因表达的机制，从而抑制细胞凋亡、肿瘤进展和化疗或放射抗性。由于这些研究将阐明肺癌中最常见的促生存和致癌因子调节 PTEN 肿瘤抑制基因的新机制，因此这些发现可能会导致干预策略的开发，这些策略可以消除 NF-κB 或激活 Ras 诱导的抗凋亡途径，从而恢复 PTEN 的表达和促凋亡潜力。