Rapid transcriptional Down-regulation of c-myc expression during cyclic adenosine monophosphate-promoted differentiation of leukemic cells

A. Slungaard, D. L. Confer, W. H. Schubach

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

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 constituitively expressed in HL-60. We find that cyclic AMP elevation in HL-60 caused by three different pharmacologic regimens is followed by an abrupt, >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.

Original languageEnglish (US)
Pages (from-to)1542-1547
Number of pages6
JournalJournal of Clinical Investigation
Volume79
Issue number5
DOIs
StatePublished - 1987

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