Changes in gene expression associated with induced differentiation of erythroleukemia: protooncogenes, globin genes, and cell division.
Changes in gene expression associated with induced differentiation of erythroleukemia: protooncogenes, globin genes, and cell division.
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DOI：
10.1073/pnas.83.18.6849
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发表时间：
1986-09
影响因子：
11.1
通讯作者：
R. Ramsay;K. Ikeda;R. Rifkind;P. Marks
中科院分区：
文献类型：
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作者：
R. Ramsay;K. Ikeda;R. Rifkind;P. Marks
六亚甲基双乙酰胺(HMBA)诱导小鼠红白血病细胞(Melc)分化是一个多步骤的过程，包括一个早期潜伏期，在此期间已检测到一系列代谢变化，但细胞尚未不可逆转地致力于分化。承诺被定义为当HMBA从培养中去除后，Melc继续表达最终细胞分裂和基因表达程序的能力(如珠蛋白mRNA的积累)。在HMBA存在的情况下，一小部分MELC在10-12小时内承诺，而在48-60小时前超过90%。本研究表明，在培养的最初4小时内，HMBA导致c-myb和c-myc的表达显著降低，而c-fos的mRNA表达水平显著升高。随着培养时间的延长，c-myb的减少和c-fos mRNA的增加持续存在，而c-myc的mRNA在Melc开始出现不可逆转的分化之前恢复到对照水平。地塞米松阻断HMBA诱导的Melc分化的表达，不改变原癌基因mRNA的早期变化模式，也不改变c-fos的持续升高，但它确实抑制了对c-myb的持续抑制，使c-myb恢复到对照水平。氯化血红素诱导Melc积累珠蛋白，但不会启动对末端细胞分裂的承诺，不会改变这些原癌基因的mRNA水平。这些研究表明，尽管c-myb和c-myc的早期减少和c-fos mRNAs的增加可能参与了导致分化的多步事件，但c-myb的持续抑制对于HMBA诱导的Melc向末端细胞分裂的承诺至关重要。
Hexamethylenebisacetamide (HMBA)-induced differentiation of murine erythroleukemia cells (MELC) is a multistep process involving an early latent period during which a number of metabolic changes have been detected, but the cells are not yet committed irreversibly to differentiate. Commitment is defined as the capacity of MELC to go on to express the program of terminal cell division and gene expression (such as the accumulation of globin mRNA) upon removal of the HMBA from the culture. In the presence of HMBA, a small proportion of MELC are committed by 10-12 hr and greater than 90% by 48-60 hr. The present study shows that, during the initial 4 hr of culture, HMBA causes a marked decrease in c-myb and c-myc and an increase in c-fos mRNA levels. With continued culture, the decrease in c-myb and the increase in c-fos mRNA persists, while c-myc mRNA returns to control levels before the time that MELC begin to show irreversible differentiation. Dexamethasone, which blocks expression of HMBA-induced MELC differentiation, does not alter the early pattern of changes in protooncogene mRNA nor the sustained elevation of c-fos, but it does inhibit the continued suppression of c-myb allowing c-myb to return toward control levels. Hemin, which induces MELC to accumulate globins but does not initiate commitment to terminal cell division, does not alter these protooncogene mRNA levels. These studies suggest that, although the early decrease in c-myb and c-myc and increase in c-fos mRNAs may be involved in the multistep events leading to differentiation, the continued suppression of c-myb is critical for HMBA-induced MELC commitment to terminal cell division.