PHARMACOLOGIC REGULATION OF GENE EXPRESSION IN LEUKEMIA

白血病基因表达的药理学调控

基本信息

批准号：
3079582
负责人：
MATTHEW L SHERMAN
金额：
$ 7.54万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-06-01 至 1990-05-31
项目状态：
已结题

项目摘要

The polyamines putrescine, spermidine and spermine have been implicated in the regulation of cellular proliferation and differentiation. However, a direct role has been demonstrated only for spermidine in DNA replication. We have previously shown that spermidine is required for both murine erythroleukemia (MEL) cell proliferation and induction of differentiation. Furthermore, we have demonstrated that spermidine is required for both the induction of heme synthesis and transcription of alpha- and beta-globin mRNA. The requirement of spermidine for induction of MEL differentiation may reflect the necessity of cell division for expression of the mature phenotype. The biosynthesis of spermidine and spermine is associated with the formation of 5'-methylthioadenosine (MTA). We have recently demonstrated that MTA inhibits induction of MEL differentiation. This effect was not associated with spermidine depletion or cytostasis. MTA is a known inhibitor of S-adenosylhomosysteine hydrolase and DNA methylation and may inhibit induction of differentiation by interfering with transmethylation reactions. MTA also inhibits cyclic AMP phosphodiesterase activity and potentiates the cellular cAMP response to adenylate cyclase activators. Therefore, this naturally occurring nucleoside may be an intermediate involved in the interrelationships between cellular proliferation and specific gene expression. The proposed studies will thus extend our work on the involvement of polyamines in leukemic cell proliferation and differentiation. The initial studies will monitor the effects of MTA on MEL intracellular S-adenosylmethionine metabolism, nucleic acid methylation, and intracellular cAMP metabolism. A more precise understanding of the biochemical basis for regulating MEL commitment to differentiation will be explored by using MTA analogues and other inhibitors of S-adenosylhomocysteine hydrolase. This work should provide the basis for monitoring the effects of MTA and MTA analogues on transcription and DNA methylation of specific MEL genes including alpha-globin, beta- globin and mouse c-myc. Since previous studies have also demonstrated that spermidine is required for induction of human HL-60 leukemic cell differentiation, the proposed work will thus also monitor the effects of MTA on methylation and expression of specific genes (c-myc, c-fos) in this cell line. These studies should be important in providing a basis for understanding biochemical interrelationships between proliferation and differentiation in leukemic cells.

多胺腐霉，精子和精子已经与细胞增殖的调节有关分化。但是，已经证明了直接角色仅用于DNA复制中的精子。我们以前有表明两种鼠都需要精子红血球血症（MEL）细胞增殖和诱导分化。此外，我们已经证明了血红素合成既需要精子以及α-和β-珠蛋白mRNA的转录。这精子诱导MEL分化的要求可能反映了细胞分裂表达的必要性成熟表型。精子和精子的生物合成与形成5'-甲基噻可腺苷（MTA）。我们最近有证明MTA抑制了MEL分化的诱导。这种作用与精子耗竭或 cytostasis。 MTA是已知的s-腺苷氢糖素抑制剂水解酶和DNA甲基化，可能抑制诱导通过干扰跨甲基化反应的分化。 MTA还抑制环状AMP磷酸二酯酶活性和增强细胞cAMP对腺苷酸环化酶的反应激活剂。因此，这种天然存在的核苷可能是参与相互关系的中间人细胞增殖和特定基因表达。因此，拟议的研究将扩大我们在参与方面的工作白血病细胞增殖和分化中的多胺。最初的研究将监测MTA对MEL的影响细胞内S-腺苷甲硫代代谢，核酸甲基化和细胞内cAMP代谢。更精确对调节MEL的生化基础的理解使用MTA将探讨对差异化的承诺类似类似物和其他抑制剂的s-腺苷同生半胱氨酸水解酶。这项工作应为监视 MTA和MTA类似物对转录和DNA的影响特定MEL基因在内的甲基化，包括α-珠蛋白，β- 球蛋白和小鼠C-Myc。由于以前的研究也证明精子是诱导人需要的 HL-60白血病细胞分化，拟议的工作将还监测MTA对甲基化和表达的影响该细胞系中的特定基因（C-Myc，c-fos）。这些研究对于为提供基础很重要了解生化相互关系白血病细胞的增殖和分化。