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号染色体上缺失的磷酸酶和紧张素同源物）是PI-3激酶/Akt依赖性细胞存活途径的负调控因子。PTEN位于染色体10q23上的一个区域，在许多人类癌症中显示出杂合性的丧失，PTEN基因功能在多种癌症中由于PTEN的突变或染色体10q23的缺失而丧失。然而，在非小细胞肺癌、甲状腺癌等几种癌症中，PTEN基因是完整的野生型，但其表达减少。由于PTEN的单倍体不足与肿瘤发生有关，因此了解PTEN的表观遗传下调机制具有重要的临床意义和基础意义。最近的研究表明，PTEN伪基因而非野生型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，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Egr-1本身抑制PTEN基因的表达。

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.