The c-ets-1 proto-oncogene is a new early-response gene differentially regulated by cytokines and growth factors in human fibroblasts.
In various invasive human tumors, c-ets-1 mRNA was found to be selectively expressed in stromal fibroblasts. We have now investigated the possibility that soluble factors could regulate c-ets-1 expression in cultured human fibroblasts. We show that both conditioned media from tumor cell lines and a number of characterized cytokines and growth factors were able to induce c-ets-1 expression. TNF alpha and IL-1 alpha were the most potent c-ets-1 stimulators, inducing rapid (within 1 h) and long-lasting (19 h) increases of c-ets-1 mRNA and protein expression. In contrast, bFGF, EGF, and PDGF were mainly delayed stimulators, with maximal stimulation being detected by 19 h. In addition, these growth factors potentiated the rapid induction of c-ets-1 by TNF alpha. While all these factors were able to stimulate c-ets-1 expression, TGF beta was found to be ineffective. Using inhibitors of transcription and translation, we also found that increase of c-ets-1 mRNA by TNF alpha resulted from new transcription rather than from stabilization and did not require new protein synthesis. These results demonstrated that c-ets-1 is a new nuclear target for several factors and behaves as an early-response gene for TNF alpha.
Gilles
F
F
Unité d'Oncologie Moléculaire (CNRS URA 1160), Institut Pasteur de Lille, France.
Raes
M B
MB
Stéhelin
D
D
Vandenbunder
B
B
Fafeur
V
V
D002478:Cells, Cultured / Q000166:cytology / Q000201:enzymology; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007231:Infant, Newborn; D007375:Interleukin-1 / Q000494:pharmacology; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger / Q000032:analysis; D012867:Skin / Q000166:cytology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000201:enzymology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D006133:Growth Substances; D007375:Interleukin-1; C000715470:MAS1 protein, human; D010982:Platelet-Derived Growth Factor; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases