Modulation of SAM levels in leukemic cells

白血病细胞中 SAM 水平的调节

• 批准号: 7744458
• 负责人: Malak Y.S. Kotb
• 金额: $ 9.42万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7744458
• 关键词: Affect; B-Lymphocytes; Biological; Blood; Cell Line; Cells; Chemicals; Chiroptera; Data; Differentiation and Growth; Drops; Drug Delivery Systems; Enzymes; Extrahepatic; Gene Expression; Goals; Growth; Hematopoietic; Homocysteine; Homocystine; Human; Isoenzymes; Lead; Leukemic Cell; Lipids; Liver; Malignant - descriptor; Malignant Neoplasms; Mammals; Metabolic; Metabolism; Methylation; Molecular; Normal Cell; Nucleic Acids; Numbers; Pharmaceutical Preparations; Physiological; Polyamines; Principal Investigator; Proteins; RNA Stability; Reaction; Regulation; Research; Rest; Role; S-Adenosylmethionine; Small Interfering RNA; T-Lymphocyte; Testing; Tissues; Translating; base; cancer cell; cell growth; inhibitor/antagonist; leukemia; methionine adenosyltransferase; programs; protein function; rapid growth; tool; tool development

DESCRIPTION (provided by applicant): Methionine adenosyltransferase (MAT) is an essential enzyme in metabolism because It catalyzes the synthesis of S-adenosylmethionine (AdoMet, SAMe), a pivotal biological molecule that functions as the major methyl donor and a precursor for homocysteine and the polyamines. AdoMet is second only to ATP in the number of reactions it participates in, or regulates. Methylation reactions regulate the function and activity of proteins, nucleic acids and lipids. Studies have shown that abnormal AdoMet levels (high or low) are associated with malignant transformations and that aberrant biological methylation can lead to cancer by affecting gene expression, RNA stability, protein function, as well as cell growth and differentiation. Because of its central role in metabolism, the synthesis of AdoMet by MAT has been targeted for inhibition by chemical drugs for years. We have used MAT inhibitors to block the growth and differentiation of human T cells, and others have shown that inhibition of AdoMet synthesis in cancer cells, including leukemic cells, significantly reduced their growth. The problem was that MAT chemical inhibitors were very difficult to synthesize in large quantities, and most were reversible and nonspecific. Our studies to date have led us to propose that AdoMet levels can be potentiated in leukemic T cells by using molecular tools that modulate the expression of MAT subunits. This application focuses on the development of these tools and the assessment of their effect in diminishing the growth of leukemic cells. We have demonstrated that MAT regulation and AdoMet metabolism are drastically different in normal and leukemic T cells. The central hypothesis is that we can exploit these physiological differences and selectively modulate AdoMet metabolism in leukemic cells in a way that halts their growth. We propose that this can be affected by potentiating the expression of the regulatory ¿ subunit of the MAT II isozyme, the only isozyme of MAT found in extrahepatic tissue.

描述（由适用提供）：蛋氨酸腺苷转移酶（MAT）是代谢中的必不可少的酶，因为它催化了S-腺苷硫代氨酸的合成（ADOMET，ADOMET，SALE，SALE），这是一种枢轴的生物分子，是主要的甲基供体，是甲基供体的主要甲基供体，并且是甲基化的前体和多胺的前体。 ADOMET仅次于ATP参与或调节的反应数量。甲基化反应调节蛋白质，核酸和脂质的功能和活性。研究表明，异常的ADOMET水平（高或低）与恶性转化有关，并且异常的生物甲基化可以通过影响基因表达，RNA稳定性，蛋白质功能以及细胞生长和分化来导致癌症。由于其在代谢中的核心作用，MAT合成ADOMET已被化学药物抑制多年。我们已经使用MAT抑制剂来阻断人T细胞的生长和分化，而其他抑制剂则表明，包括白血病细胞在内的癌细胞中ADOMEN合成的抑制作用可显着降低其生长。问题在于，MAT化学抑制剂很难大量合成，并且大多数是可逆的和非特异性的。迄今为止，我们的研究使我们提出，通过使用调节垫子亚基表达的分子工具，可以在白血病T细胞中进行ADOMET水平。该应用的重点是这些工具的开发及其对减少白血病细胞生长的影响的评估。我们已经证明，在正常和白血病T细胞中，MAT调节和ADOMET替型代谢截然不同。中心假设是，我们可以探索这些物理差异，并选择性地调节白血病细胞中的ADOMET替型，以停止其生长的方式。我们建议，这可以通过增强MAT II同工酶的调节性亚基的表达来影响，这是在肝外组织中发现的唯一MAT的同工酶。