Modulation of nuclear proto-oncogene expression and cellular growth in myeloid leukemic cells by human interferon alpha.
To address the mechanisms that regulate expression of specific growth-related nuclear proto-oncogenes, the transcript levels of the c-fos, c-myc, (2'5')-oligoadenylate synthetase, IFN-alpha 1, and IFN-beta 1 genes have been measured in the human leukemic cell lines KG-1, U937, and HL-60 following growth stimulation by serum, induction of differentiation by tumor-promoting agents, and/or treatment of cells with exogenously supplied alpha interferon (rIFN-alpha 2). Production of fos and myc RNA was measured by S1 mapping, using fos DNA probes which identified either primary unspliced transcripts or steady-state-spliced mRNA levels, and using a myc probe which spanned the two major c-myc start sites, P1 and P2. Pretreatment of a quiescent KG-1 cell population with IFN for 18 hours before serum addition decreased the stimulation of both fos and myc RNA production. In HL-60 and U937 cells, IFN pretreatment had no inhibitory effect on serum-induced fos or myc transcription; however, in U937, rIFN-alpha 2 treatment alone stimulated fos mRNA 11-fold. Expression of 2'5'oligoadenylate synthetase was induced in IFN-treated cultures but not in cells stimulated with serum alone. No serum-induced IFN-alpha 1 or IFN-beta 1 gene expression was observed in KG-1 or U937 cells. These results demonstrate that exogenous rIFN-alpha 2 treatment of quiescent KG-1 cells can antagonize the effect of growth factors by altering expression of nuclear proto-oncogenes, but in general growth inhibition is not obligatorily coupled to inhibition of proto-oncogene transcription.
Marshall
A H
AH
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
Alper
D
D
Hiscott
J
J
D002455:Cell Division; D005796:Genes; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000502:physiology*; D007938:Leukemia; D015470:Leukemia, Myeloid, Acute; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes; D012334:RNA, Neoplasm / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology*; D014158:Transcription, Genetic
D007370:Interferon Type I; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012334:RNA, Neoplasm; D011994:Recombinant Proteins