INHIBITION OF HUMAN ONCOGENE EXPRESSION BY INTERFERON

描述：（改编自研究者摘要）赖氨酰氧化酶（LO） 作为ras癌基因的致瘤性的抑制因子发挥作用。在NIH 3 T3中 LTR-C-H-ras（RS485）的多拷贝转化的细胞， LO明显下降。干扰素（INF）β长期治疗 产生了仍然过表达ras但恢复了LO表达的回复突变体。 反义赖氨酸氧化酶转染持久回复突变细胞的研究 表达构建体导致LO表达的再转化和丧失。 因为ras癌基因与几种人类癌症有关， 可以通过维持或恢复LO来预防或治疗这些癌症 表情虽然LO被认为是一种参与细胞外分泌的酶， 胶原成熟，该基因在正常上皮细胞中表达， 乳腺前列腺和结肠在源自乳腺和前列腺的人类肿瘤中 在上皮中，LO表达减少或缺乏。RAS的机制 将研究转化下调LO表达。初步 亚硫酸氢盐修饰的基因组DNA的研究表明，LO中的CpG岛 NIH 3 T3和TS 485之间启动子的甲基化差异。甲基化 NIH 3 T3、RS485和持久回复突变细胞的LO启动子模式 将被确定和比较，以阐明可能的贡献 甲基化下调LO表达。的机制 LO表达的恢复抑制了肿瘤发生ras表型， 追究除了其细胞外功能， 胶原蛋白和弹性蛋白，最近显示LO存在于细胞核中并在细胞核中具有活性， 这表明LO确实具有细胞内功能。LO缺失突变体 将用于确定哪些蛋白质结构域有助于功能性 FS 485的逆转。用IRF 1抗体的研究表明，在RS485细胞中， 有一种比IRF-1小的蛋白质也与IRF-1抗体结合。的 这两种蛋白质的关系和较小物种的贡献 将对LO转录进行研究。用一种抗肿瘤药物处理RS485细胞 IFN β和视黄酸的组合引起高百分比的 已经失去了所有的多个拷贝的转化 LTR-c-H-ras肿瘤。这种删除所涉及的机制是 因为它可能用于治疗HTLV或HIV诱导的 与LTR相关的病毒。

DESCRIPTION: (Adapted from the investigator's abstract) Lysyl oxidase (LO) functions as a suppressor of the tumorigenicity of the ras oncogene. In NIH 3T3 cells transformed by multiple copies of LTR-C-H-ras (RS485), the transcription of LO is markedly decreased. Long term treatment with interferon (INF) beta created revertants that still overexpressed ras but had restored LO expression. Transfection of persistent revertant cells with antisense lysly oxidase expression constructs led to retransformation and loss of LO expression. Because the ras oncogene is involved in several human cancers, it might be possible to prevent or treat such cancers by maintaining or restoring LO expression. Although LO is known as a secreted enzyme involved in extracellular collagen maturation, the gene is expressed in normal epithelial cells of breast, prostate, and colon. In human tumors derived from breast and prostate epithelium, LO expression is reduced or lacking. The mechanism(s) by which ras transformation down regulates LO expression will be studied. Preliminary studies of bisulfite modified genomic DNA suggest that the CpG island in the LO promoter is differentially methylated between NIH 3T3 and TS485. Methylation patterns in the LO promoter of NIH 3T3, RS485, and persistent revertant cells will be determined and compared to elucidate the possible contribution of methylation to the down regulation of LO expression. The mechanism by which restoration of LO expression suppressed the tumorigenic ras phenotype will also be investigated. In addition to its extracellular function in the maturation of collagen and elastin, LO was recently shown to be present and active in nuclei, suggesting that LO does have an intracellular function. LO deletion mutants will be used to determine which protein domains contribute to the functionality of reversion of FS485. Studies with antibody to IRF1 showed that in RS485 cells there was a protein smaller than IRF-1 that also bound IRF-1 antibody. The relationship of these two proteins and the contribution of the smaller species to LO transcription will be investigated. Treatment of RS485 cells with a combination of IFN beta and retinoic acid gave rise to a high percentage of revertants that had lost all of the multiple copies of the transforming LTR-c-H-ras oncogence. The mechanism involved in this deletion will be investigated as it might be useful for the treatment of HTLV or HIV induced diseases, which involve LTR-linked viruses.