Rapid transcriptional down-regulation of c-myc expression during cyclic adenosine monophosphate-promoted differentiation of leukemic cells.
Rapid transcriptional down-regulation of c-myc expression during cyclic adenosine monophosphate-promoted differentiation of leukemic cells.
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在环磷酸腺苷促进白血病细胞分化过程中，c-myc 表达快速转录下调。
DOI：
10.1172/jci112987
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发表时间：
1987
期刊：
影响因子：
--
通讯作者：
Schubach,WH
中科院分区：
文献类型：
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作者：
Slungaard,A;Confer,DL;Schubach,WH
在多种转化的哺乳动物细胞中，包括HL-60人早幼粒细胞白血病细胞系，环AMP （cAMP）的药理学升高可促进生长停滞和分化。然而，人们对这一现象背后的机制知之甚少。由于细胞癌基因在调节增殖和分化中起着关键作用，我们研究了camp促进HL-60分化之前是否存在c-myc表达的减少，c-myc是HL-60中扩增和组成性表达的细胞癌基因。我们发现，三种不同的药物方案导致HL-60中环AMP升高，随后在3小时内，稳态c-myc mRNA水平突然下降90%以上，远远早于可检测到的增殖和分化变化。尽管蛋白合成阻断，这种减少仍然发生，这是由于c-myc的转录下调，并伴随着c-myc启动子位点附近染色质结构的变化。我们的研究结果表明，cAMP是一种普遍存在的细胞内调节信使，以前只知道在高级真核细胞中增强基因转录活性，也可以抑制细胞癌基因的转录，从而提示cAMP促进分化的潜在机制。图片
Pharmacologic elevation of cyclic AMP (cAMP) promotes growth arrest and differentiation in a variety of transformed mammalian cells, including the HL-60 human promyelocytic leukemia cell line. However, mechanisms underlying this phenomenon are poorly understood. Because cellular oncogenes play a pivotal role in regulating proliferation and differentiation, we examined whether cAMP-promoted differentiation of HL-60 was preceded by a decrease in the expression of c-myc, a cellular oncogene both amplified and constitutively expressed in HL-60. We find that cyclic AMP elevation in HL-60 caused by three different pharmacologic regimens is followed by an abrupt, greater than 90% decrease in steady state c-myc mRNA levels within 3 h, well before detectable changes in proliferation and differentiation. This decrease, which occurs despite protein synthetic blockade, is attributable to transcriptional down-regulation of c-myc and is accompanied by changes in chromatin structure near c-myc promoter sites. Our findings establish that cAMP, a ubiquitous intracellular regulatory messenger previously known only to enhance gene transcriptional activity in higher eukaryotic cells, can also suppress transcription of a cellular oncogene, thereby suggesting a potential mechanism for cAMP-promoted differentiation.Images