Recombinant human tumor necrosis factor alpha regulates c-myc expression in HL-60 cells at the level of transcription.
Recombinant human tumor necrosis factor alpha (TNF alpha) effectively inhibits clonal growth of leukemic cells from patients and several cell lines, including the promyelocytic HL-60 cells. Decreased expression of the c-myc oncogene is linked to growth arrest and terminal cellular differentiation. The present study characterizes the effect of TNF alpha on the regulation of the c-myc gene in HL-60 cells. TNF alpha (100 U/mL) rapidly inhibited messenger RNA (mRNA) accumulation of c-myc with a 50% reduction in less than one hour. Dose-response studies showed that a 50% reduction of c-myc mRNA occurred in the range of 15 U/mL. In vitro nuclear run-on experiments showed that this decrease of c-myc-mRNA accumulation was the result of a reduced rate of transcription of c-myc by TNF alpha. Further studies demonstrated that TNF alpha did not post-transcriptionally alter levels of c-myc mRNA, and the inhibitory action of TNF alpha on c-myc expression in HL-60 cells did not depend on new protein synthesis. In the conditions of all the experiments, TNF alpha did not affect cell viability. By contrast, TNF alpha (500 U/mL) did not decrease mRNA levels of c-myc in an HL-60 variant cell line whose growth was not inhibited by TNF alpha; also TNF alpha (500 U/mL) increased c-myc-mRNA levels in normal fibroblasts whose growth is known to be stimulated by TNF alpha. These findings, in concert with prior studies, show a close association between growth inhibition of HL-60 cells and decreased levels of mRNA coding for c-myc.
Tobler
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Johnston
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Koeffler
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D002460:Cell Line; D002478:Cells, Cultured; D003101:Collodion; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D009857:Oncogenes / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha
D006023:Glycoproteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003101:Collodion