The antimitogenic action of tumor necrosis factor is associated with increased AP-1/c-jun proto-oncogene transcription.
Tumor necrosis factor alpha (TNF) mediates its in vivo antineoplastic effect primarily through its action on the endothelial surfaces of tumor vessels. Among other changes, endothelial cells increase the expression of surface procoagulant molecules which allow for the genesis of microthrombi and the eventual anoxic killing of the tumor tissue. TNF is also a potent antimitotic factor for endothelial cells. We investigated the molecular basis for these diverse actions of TNF by differential screening of a cDNA library prepared from TNF and cycloheximide-treated human umbilical vein endothelial (HUVE) cells. One of the cDNA clones identified encodes the transcription factor and proto-oncogene AP-1/c-jun. The expression of AP-1/c-jun following TNF treatment is mediated largely at the transcriptional level. Neither c-myc nor c-fos transcripts were induced by TNF. Since AP-1/c-jun has been previously identified as one of the earliest transcripts expressed in quiescent cells that have been stimulated by growth factors, our results suggest that mitogenic and antimitogenic stimuli evoke distinct yet overlapping sets of molecular responses and that the coordinate expression of AP-1/c-jun and c-fos is not mandatory. AP-1/c-jun transcript induction is thus one of the initial events mediated by TNF treatment of HUVE cells.
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VM
Department of Pathology, University of Michigan School of Medicine, Ann Arbor 48109.
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D015152:Blotting, Northern; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun; D011519:Proto-Oncogenes / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins
D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D004247:DNA