EFFECTS OF CHRONIC 5'-([(Z)-4-AMINO-2-BUTENYL]METHYLAMINO)-5'-DEOXY-ADENOSINE (ABEADO) TREATMENT ON POLYAMINE AND EIF-5A METABOLISM IN ABEADO-SENSITIVE AND ABEADO-RESISTANT L1210 MURINE LEUKEMIA-CELLS
EFFECTS OF CHRONIC 5'-([(Z)-4-AMINO-2-BUTENYL]METHYLAMINO)-5'-DEOXY-ADENOSINE (ABEADO) TREATMENT ON POLYAMINE AND EIF-5A METABOLISM IN ABEADO-SENSITIVE AND ABEADO-RESISTANT L1210 MURINE LEUKEMIA-CELLS
复制标题
DOI：
10.1042/bj2900115
复制
发表时间：
1993-02-15
影响因子：
4.1
通讯作者：
PEGG, AE
中科院分区：
文献类型：
--
作者：
BYERS, TL;WIEST, L;PEGG, AE
我们之前曾报道过，长期长期暴露于 S-腺苷-L-甲硫氨酸脱羧酶 (AdoMetDC) 抑制剂 5'-{[(Z)-4-氨基-2-丁烯基]甲基氨基}-5'-脱氧腺苷 (MDL 73811, AbeAdo)，会导致 L1210 细胞细胞停滞 [Byers, Ganem 和 Pegg (1992) Biochem. J.287.717-724]。通过比较对 AbeAdo 具有抗性的 L1210 衍生细胞系 (R20) 与亲本细胞，进一步研究了产生这些作用的机制。 R20 细胞是通过两轮 AbeAdo 诱导的细胞抑制，然后用外源多胺拯救而衍生的。用 10 muM AbeAdo 处理 L1210 细胞 12 天，诱导细胞停滞；然而，暴露于高达 40 muM AbeAdo 不会诱导 R20 细胞出现细胞停滞。在经处理的 L1210 和经处理的 R20 细胞中，腐胺水平升高，精胺水平减少。经处理的 L1210 细胞中亚精胺被耗尽，但经处理的 R20 细胞中仅部分减少。在处理的 L1210 细胞中，AdoMetDC 活性低于检测限，但尽管大大降低，但可以在处理的 R20 细胞中测量到。 R20细胞对AbeAdo对细胞生长和亚精胺消耗的影响的抵抗力与R20细胞的AbeAdo积累减少相关。在没有亚精胺合成的情况下。 AbeAdo 处理的 L1210 细胞中积累了未抑制的真核翻译起始因子 5A (eIF-5A)。 R20 细胞中未检测到未羟丁化的 eIF-5A 积累。在 AbeAdo 治疗期间积累的未hypuslated eIF-5A 在被外源亚精胺拯救的L1210 细胞中被耗尽。这些发现与 AbeAdo 诱导的细胞停滞是由于 hypusinated eIF-5A 丢失所致的假设一致。然而，精胺能够拯救 AbeAdo 处理的 L1210 细胞，而不会显着减少 AbeAdo 处理期间积累的未修饰的 eIF-5A，这表明只需少量未修饰的蛋白质必须被修饰以恢复细胞生长。
We have previously reported that prolonged chronic exposure to the S-adenosyl-L-methionine decarboxylase (AdoMetDC) inhibitor, 5'-{[(Z)-4-amino-2-butenyl]methylamino}-5'-deoxyadenosine (MDL 73811, AbeAdo), leads to cytostasis of L1210 cells [Byers, Ganem and Pegg (1992) Biochem. J. 287. 717-724]. Further studies to investigate the mechanism by which these effects are brought about were carried out by comparing an L1210-derived cell line (R20) that is resistant to AbeAdo with the parent cells. The R20 cells were derived by two rounds of AbeAdo-induced cytostasis followed by rescue with exogenous polyamines. Cytostasis was induced in L1210 cells treated for 12 days with 10 muM AbeAdo; however, exposure to up to 40 muM AbeAdo did not induce cytostasis in R20 cells. Putrescine levels were elevated and spermine levels were depleted in both treated L1210 and treated R20 cells. Spermidine was depleted in treated L1210 cells but was only partly reduced in treated R20 cells. AdoMetDC activity was below the limit of detection in treated L1210 cells but, although greatly reduced, could be measured in the treated R20 cells. The resistance of the R20 cells to the effects of AbeAdo on cell growth and spermidine depletion correlated with reduced AbeAdo accumulation by R20 cells. In the absence of spermidine synthesis. unhypusinated eukaryotic translation initiation factor 5A (eIF-5A) accumulated in AbeAdo-treated L1210 cells. There was no detectable accumulation of unhypusinated eIF-5A in R20 cells. Unhypusinated eIF-5A accumulated during AbeAdo treatment was depleted in L1210 cells rescued by exogenous spermidine. These findings are consistent with the hypothesis that AbeAdo-induced cytostasis is due to the loss of hypusinated eIF-5A. However, spermine was able to rescue AbeAdo-treated L1210 cells without significantly reducing the unhypusinated eIF-5A accumulated during AbeAdo treatment, suggesting that only a small amount of the unmodified protein must be hypusinated to restore cell growth.