INHIBITION OF HUMAN ONCOGENE EXPRESSION BY INTERFERON

干扰素对人类癌基因表达的抑制

• 批准号: 6632930
• 负责人: ROBERT M FRIEDMAN
• 金额: $ 18.5万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6632930
• 关键词: 3T3 cells; CpG islands; DNA methylation; amine oxidoreductase; collagen; elastin; enzyme activity; gene induction /repression; genetic transcription; guanine nucleotide binding protein; human tissue; interferon beta; neoplasm /cancer genetics; neoplastic transformation; oncogenes

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.

描述：(改编自调查人员摘要)赖氨酰氧化酶(LO) 发挥抑制ras癌基因致瘤性的作用。在NIH 3T3中 多拷贝LTR-C-H-ras(RS485)转化细胞的转录 LO显著降低。长期使用干扰素(INF)β治疗 创建了仍过表达ras但恢复了Lo表达的回复突变体。 反义赖氨酸氧化酶基因转导永久性逆转细胞的研究 表达载体的构建导致LO表达的重新转化和丢失。 因为ras癌基因与几种人类癌症有关，所以它可能是 有可能通过保持或恢复Log来预防或治疗此类癌症 表情。尽管LO被认为是一种与细胞外有关的分泌酶 胶原蛋白成熟时，该基因在正常皮肤上皮细胞中表达 乳房、前列腺和结肠。来自乳腺和前列腺的人类肿瘤 上皮细胞，LO表达减少或缺失。RAS的作用机制(S) 向下调节LO表达的转化将被研究。初步 亚硫酸氢盐修饰的基因组DNA研究表明，LO中的CpG岛 启动子在NIH 3T3和TS485之间存在差异甲基化。甲基化 NIH3T3、RS485和持续突变细胞LO启动子的模式 将被确定和比较，以阐明可能的贡献 甲基化对LO表达的下调作用。这一机制通过它 恢复LO表达抑制的致瘤ras表型也将 被调查。除了它在细胞外成熟过程中的功能外 胶原和弹性蛋白，LO最近被证明存在于细胞核中并活跃， 这表明LO确实具有细胞内功能。LO缺失突变体 将被用来确定哪些蛋白质结构域对功能有贡献 FS485的恢复。对IRF1抗体的研究表明，在RS485细胞中 有一种比IRF-1小的蛋白质也能与IRF-1抗体结合。这个 这两种蛋白质的关系及较小物种的贡献 将对TO LO转录进行调查。阿糖胞苷对RS485细胞的作用 干扰素β和维甲酸的结合导致了高比例的 丢失了所有转换的多个副本的返回体 Ltr-c-h-ras融合。这一删除涉及的机制将是 研究认为它可能对治疗HTLV或HIV感染有用 疾病，其中涉及与LTR相关的病毒。

项目成果

Deregulated expression of interferon regulatory factor-1 in oncogene-transformed mouse fibroblasts.

致癌基因转化的小鼠成纤维细胞中干扰素调节因子 1 的表达失调。

• DOI: 10.1089/107999003322558773
• 发表时间: 2003
• 期刊: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.
• 作者: Contente,Sara;Attard,FrankA;Yeh,Tze-JouAnnie;Buchhagen,DorothyL;Friedman,RobertM
• 通讯作者: Friedman,RobertM

Structure of the mouse lysyl oxidase gene.

小鼠赖氨酰氧化酶基因的结构。

• DOI: 10.1006/geno.1993.1202
• 发表时间: 1993
• 期刊: Genomics
• 影响因子: 4.4
• 作者: Contente,S;Csiszar,K;Kenyon,K;Friedman,RM
• 通讯作者: Friedman,RM

H-ras localizes to cell nuclei and varies with the cell cycle.

• DOI: 10.1177/1947601911405042
• 发表时间: 2011-02-01
• 期刊: Genes & cancer
• 作者: Contente, Sara;Yeh, Tze-Jou Annie;Friedman, Robert M
• 通讯作者: Friedman, Robert M

Post-transcriptional regulation by interferon-alpha of epsilon-globin production in human erythroleukemia K-562 cells.

干扰素-α 对人红白血病 K-562 细胞中 epsilon-珠蛋白产生的转录后调节。

• DOI: 10.1089/jir.1992.12.311
• 发表时间: 1992
• 期刊: Journal of interferon research
• 作者: Friedman,RM;Yeh,A;Tang,W
• 通讯作者: Tang,W

Identification of proteins immunologically related to interferon regulatory factor-1 that bind with interferon regulatory factor element.

鉴定免疫学上与干扰素调节因子-1 相关且与干扰素调节因子元件结合的蛋白质。

• DOI: 10.1086/505358
• 发表时间: 2006
• 期刊: The Journal of infectious diseases.
• 作者: Contente,Sara;Attard,FrankA;Friedman,RobertM
• 通讯作者: Friedman,RobertM