Novel Mechanisms of PTEN Gene Regulation

描述(申请人提供)：促凋亡肿瘤抑制基因PTEN(10号染色体缺失的磷酸酶和Tensin同源物)是PI-3激酶/Akt依赖的细胞生存途径的负调控因子。PTEN位于染色体10q23上，在许多人类肿瘤中表现为杂合性缺失，在多种肿瘤中，PTEN基因功能的丧失可能是由于PTEN的突变或染色体10q23的缺失。然而，在非小细胞肺癌和甲状腺癌等几种癌症中，PTEN基因是完整的和野生型的，但其表达减弱。由于PTEN基因的缺失与肿瘤的发生有关，了解表观遗传学下调PTEN基因的机制(S)具有重要的临床意义和基础意义。最近的研究表明，PTEN假基因而不是野生型PTEN基因发生了甲基化，表明DNA甲基化不是导致PTEN启动子沉默导致PTEN基因表达降低的潜在机制。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控因子NF-kappaB和致癌RAS下调PTEN的表达。有趣的是，致癌RAS上调转录因子Egr-1的表达，而转录因子Egr-1本身抑制PTEN基因的表达。 这里提出的研究将解决下调PTEN基因表达的机制，这些机制与功能相关，即它们导致磷酸化Akt水平升高和抗凋亡。我们将确定核因子-kappaB(Aim 1)和致癌RAS(Aim 2)抑制PTEN基因表达的机制，后者具有抑制细胞凋亡、肿瘤进展和化疗或放射耐受的作用。由于这些研究将阐明肺癌中最常见的促生存和致癌因素对PTEN抑癌基因调控的新机制，这些发现可能导致开发干预策略，可以去除NF-kappaB或激活的RAS诱导的抗凋亡通路，从而恢复PTEN的表达和促凋亡潜力。

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.