Retinoic acid treatment induces apoptosis or expression of a more differentiated phenotype on different fractions of cultured fetal rat hepatocytes
Retinoic acid treatment induces apoptosis or expression of a more differentiated phenotype on different fractions of cultured fetal rat hepatocytes
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DOI：
10.1002/hep.510280319
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发表时间：
1998-09-01
期刊：
影响因子：
13.5
通讯作者：
Devirgiliis, LC
中科院分区：
文献类型：
--
作者：
Falasca, L;Favale, A;Devirgiliis, LC
本文报道了维甲酸(RA)对培养的胎鼠肝细胞的影响。结果表明，维甲酸处理可诱导肝细胞分化和凋亡，在5MU/L维甲酸存在下培养48小时的肝细胞在相邻细胞接触区形成连接复合体，并形成胆小管，这是成熟细胞和分化良好的细胞的典型特征。同时，约有20%的细胞被细胞凋亡诱导死亡，并且随着RA的使用浓度和治疗时间的延长，凋亡细胞的比例增加。在形态和生化水平上对细胞凋亡的诱导研究表明，在我们的系统中，经典的染色质致密化只发生在过程的最后阶段；而不是共同的凋亡标志，即DNA梯形碎裂模式，发现了百万碱基大小的片段。这些观察结果进一步证明了不同类型细胞的凋亡机制存在根本性差异。为了探讨RA作用的分子机制，我们检测了c-myc和P53这两种已知参与细胞分化和凋亡的蛋白的表达，结果表明，RA治疗后P53的含量没有变化。相反，c-myc水平呈剂量依赖性降低，提示RA的作用可能是通过调节该癌基因来实现的。我们在成人肝细胞中未发现的RA诱导细胞凋亡的研究结果提示，这一现象可能与肝细胞的增殖能力和/或分化状态有关。
The present study reports the effects of retinoic acid (RA) on cultured fetal rat hepatocytes. We show that RA treatment induces both differentiation and apoptosis, Hepatocytes cultured for 48 hours in the presence of 5 mu mol/L RA form junctional complexes in the areas of contact between neighboring cells and develop bile canaliculi, typical features of mature and well-differentiated cells. At the same time, about 20% of cells are induced to die by apoptosis, and the percentage of apoptotic cells increases according to the concentration of RA used and the duration of treatment. The induction of apoptosis, studied at the morphological and biochemical levels, revealed that, in our system, the classical compaction of chromatin occurs only during the final stages of the process; instead of the common marker of apoptosis, i.e., the "DNA ladder" pattern of fragmentation, megabase-sized fragments were found. These observations provide further evidence of the existence of fundamental differences in the mechanisms of apoptosis among cell types. To investigate the molecular mechanism of the effects of RA, we evaluated the expression of two proteins, c-myc and p53, which are known to be involved in both cell differentiation and apoptosis, The data obtained show that the amount of p53 remained unchanged after RA treatment. On the contrary, a dose-dependent reduction in c-myc levels was found, suggesting that RA action may be mediated by modulation of this oncogene. Our findings regarding the apoptosis-inducing effect of RA, which was not found in adult hepatocytes, suggest a possible relationship between this phenomenon and the proliferative capacity and/or differentiation state of hepatocytes.