Amino acid control of asparagine synthetase: Relation to asparaginase resistance in human leukemia cells
Amino acid control of asparagine synthetase: Relation to asparaginase resistance in human leukemia cells
复制标题
DOI：
10.1152/ajpcell.1997.272.5.c1691
复制
发表时间：
1997-05-01
影响因子：
5.5
通讯作者：
Kilberg, MS
中科院分区：
文献类型：
--
作者：
Hutson, RG;Kitoh, T;Kilberg, MS
哺乳动物细胞中氨基酸的完全剥夺会导致许多重要细胞活动的基因表达显着增强；其中包括天冬酰胺合成酶（AS）。所提供的数据表明，在非白血病细胞（大鼠 Fao 肝癌细胞）和人白血病细胞（MOLT-4、NALL-1 和 BALL-1）中，在缺乏单一氨基酸的完整组织培养基或通过添加天冬酰胺酶而耗尽氨基酸天冬酰胺的培养基中孵育后，AS mRNA 水平、蛋白质含量和酶活性均被诱导。完全的氨基酸剥夺会导致 AS mRNA、蛋白质和酶活性的协同增加，这与之前发表的研究相结合表明，这种细胞反应的机制涉及 RS 基因的转录控制。天冬酰胺酶治疗是急性淋巴细胞白血病治疗的标准组成部分，其有效性与这些细胞无法将 AS 活性上调至足够的水平有关。三种人白血病细胞系的天冬酰胺酶敏感性与AS表达程度呈反比关系。无论细胞是直接通过天冬酰胺酶处理选择还是从培养基中除去天冬酰胺，对天冬酰胺酶抗性MOLT-4亚系的选择都会导致AS mRNA和蛋白质含量增加。总的来说，数据表明，天冬酰胺酶治疗的进一步进展将需要更多关于 AS 基因表达的氨基酸依赖性调节的知识，相反，天冬酰胺酶耐药性代表了在临床相关环境中研究代谢控制的模型系统。
Complete amino acid deprivation in mammalian cells causes a significant enhancement in gene expression for a number of important cellular activities; among these is asparagine synthetase (AS). The data presented demonstrate that, in both nonleukemic (rat Fao hepatoma cells) and human leukemia cells (MOLT-4, NALL-1, and BALL-1), AS mRNA levels, protein content, and enzymatic activity are induced after incubation in an otherwise complete tissue culture medium that is deficient in a single amino acid or in medium that has been depleted of the amino acid asparagine by the addition of asparaginase. Complete amino acid deprivation results in a concerted increase in AS mRNA, protein, and enzymatic activity, which, in conjunction with previously published research, suggests that the mechanism of this cellular response involves transcriptional control of the RS gene. Asparaginase treatment is a standard component of acute lymphoblastic leukemia therapy for which the effectiveness is related to the inability of these cells to upregulate AS activity to a sufficient level. With regard to the asparaginase sensitivity of the three human leukemia cell lines, there was a trend toward an inverse relation to the degree of AS expression. Selection for asparaginase-resistant MOLT-4 sublines resulted in enhanced AS mRNA and protein content regardless of whether the cells had been selected by asparaginase treatment directly or asparagine was removed from the culture medium. Collectively, the data illustrate that further advances in asparaginase therapy will require additional knowledge of amino acid-dependent regulation of AS gene expression and, conversely, that asparaginase resistance represents a model system for investigating metabolite control in a clinically relevant setting.