Novel Mechanisms of PTEN Gene Regulation

描述（由申请人提供）：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10 q23上，在许多人类癌症中显示杂合性丢失的区域内，并且在多种癌症中通过PTEN的突变或染色体10 q23的缺失而丢失PTEN基因功能。然而，在一些癌症如非小细胞肺癌和甲状腺癌中，PTEN基因是完整的和野生型的，但其表达减少。由于PTEN的单倍缺陷与肿瘤的发生有关，因此了解PTEN表观遗传下调的机制具有重要的临床和基础意义。最近的研究表明，PTEN假基因而不是野生型PTEN基因是甲基化的，表明DNA甲基化不是导致PTEN基因表达减少的PTEN启动子沉默的潜在机制。我们的初步研究表明，抗凋亡转录调节因子NF-κ B和致癌Ras在肺癌中过表达和激活，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本身又抑制PTEN基因的表达。 本文提出的研究将解决功能相关的PTEN基因表达下调的机制;即，它们导致磷酸化Akt水平升高和抗凋亡。我们将确定NF-κ B（Aim 1）和致癌Ras（Aim 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疗抗性。因为这些研究将阐明新的机制，PTEN肿瘤抑制基因的调节，最常见的肺癌中遇到的促生存和致癌因素，研究结果可能会导致干预策略的发展，可以消融NF-κ B或激活Ras诱导的抗凋亡途径，从而恢复表达和促凋亡的潜力的PTEN。

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.