Transforming growth factor-beta 1 induction of novel extracellular matrix proteins that trigger resistance to tumor necrosis factor cytotoxicity in murine L929 fibroblasts.
The molecular basis by which transforming growth factor (TGF)-beta 1 protects certain tumor cells from tumor necrosis factor (TNF) cytotoxicity was investigated. When pretreated, with TGF-beta 1, -beta 2, and -beta 3, murine L929S fibroblasts developed resistance to TNF cytotoxicity. Time course experiments revealed that TGF-beta 1 initially induced both cellular protein-tyrosine phosphorylation and simultaneous secretion of a novel extracellular matrix TNF-resistance triggering (TRT) protein(s), which closely preceded the acquisition of TNF-resistance. TGF-beta 2 and -beta 3 also increased tyrosine phosphorylation. However, both molecules failed to stimulate TRT secretion. The increased levels of phosphorylation, particularly to 9 specific protein tyrosine kinase inhibitor-sensitive cellular proteins, appeared to alter the TNF killing pathway. TGF-beta 1-induced TRT secretion required participation of unknown serum factors. TRT adhered strongly to polystyrene plates and resisted treatment with heat (60 degrees C, 30 min), collagenase, alpha 2-macroglobulin, heparin, antibodies against TGF-beta s, and limited trypsin digestion. Notably, TRT promoted TNF-resistance via activation of tyrosine and serine/threonine kinase functions in L929S. Thus, the molecular pathway involves TGF-beta 1-mediated initiation of a rapid tyrosine phosphorylation of cellular protein substrates (which alters TNF cytotoxic pathway), and a simultaneous secretion of TRT, which in turn signals the cells to maintain the levels of phosphorylation, thereby sustaining the TNF-resistance.
Chang
N S
NS
Guthrie Research Institute, Laboratory of Molecular Immunology, Guthrie Medical Center, Sayre, Pennsylvania 18840, USA.
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002396:Catechols / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D019833:Genistein; D007529:Isoflavones / Q000494:pharmacology; D007700:Kinetics; D007739:L Cells; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D019000:Phosphotyrosine; D047428:Protein Kinase Inhibitors; D019311:Staurosporine; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000633:toxicity; D000090324:Tumor Protein, Translationally-Controlled 1; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D020032:Tyrphostins
D000470:Alkaloids; D002396:Catechols; D016326:Extracellular Matrix Proteins; D007529:Isoflavones; D009570:Nitriles; D010636:Phenols; D047428:Protein Kinase Inhibitors; C000715648:Tpt1 protein, mouse; D016212:Transforming Growth Factor beta; D000090324:Tumor Protein, Translationally-Controlled 1; D020032:Tyrphostins; C060152:tyrphostin 47; D019000:Phosphotyrosine; C062898:lavendustin A; D014443:Tyrosine; D019833:Genistein; D019311:Staurosporine