title: Two distinct mechanisms of transcriptional control operate on c-myc during differentiation of HL60 cells.
abstract: We examined the mechanisms that control the downregulation of the c-myc mRNA during differentiation of HL60 cells. On treatment with dimethyl sulfoxide, HL60 cells downmodulated their steady-state c-myc message levels, ceased to proliferate, and underwent terminal differentiation. In nuclear run-on assays in which distinct segments of the c-myc gene were used as probes, an increased blocking to elongation of nascent c-myc transcripts was shown during the early phase of differentiation. During a later phase, however, a loss of transcriptional initiation was observed. This loss of promoter activity correlated well with dramatic changes in the chromatin structure of the c-myc gene, as determined by DNase I-hypersensitive site analysis. In particular, two hypersensitive sites near the two major c-myc promoters disappeared at the time that promotion abated. The newly described, later-acting negative transcriptional control of c-myc also correlated temporally with the inability to reverse the downregulation of the c-myc message quickly on withdrawal of the differentiating agent. Therefore, a terminal step during differentiation may be linked to the later-acting mode of transcriptional regulation of c-myc. The evidence presented in this report has implications for tumorigenesis in Burkitt lymphomas, in which the germ line, nontranslocated c-myc allele is transcriptionally silent.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892.
authors.forename: U
authors.initials: U
authors.lastname: Siebenlist
authors.forename: P
authors.initials: P
authors.lastname: Bressler
authors.forename: K
authors.initials: K
authors.lastname: Kelly
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003850:Deoxyribonuclease I; D005809:Genes, Regulator; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D012333:RNA, Messenger; D003850:Deoxyribonuclease I