Degradation of endothelial cell matrix collagen is correlated with induction of stromelysin by an activated ras oncogene.
A conditional expression system was established whereby the human K-ras, v-src, and v-mos genes were cloned into a conditional expression vector downstream of the dexamethasone-inducible mouse mammary tumor virus long terminal repeat. Rat-1 fibroblasts were transfected with these constructs and selected in medium containing G418. Cloned transfectants were isolated and characterized for absolute dependence on dexamethasone for expression of oncogene products and anchorage-independent growth in soft agar. Expression of activated p21K-ras(val12) enabled the fibroblasts to degrade extracellular matrix collagen secreted by murine microvessel endothelial cells. Concurrent with p21K-ras(val12) induction a proteinase with the characteristic size and substrate specificity of transin, the murine homologue of the human matrix metalloproteinase stromelysin, was expressed and secreted. Induction of v-mos and v-src oncogenes resulted in little or no detectable transin expression respectively coinciding with a relative or absolute failure to increase degradation of extracellular matrix collagen. This study suggests that in this system the expression of the ras oncogene can contribute to the in vitro invasive behavior of tumor cells by upregulating the production of a metalloproteinase capable of degrading collagen synthesized by vascular endothelial cells.
LoSardo
J E
JE
Department of Oncology, Hoffman-La Roche Inc., Nutley, NJ 07110, USA.
Goggin
B S
BS
Bohoslawec
O
O
Neri
A
A
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000502:physiology; D004790:Enzyme Induction / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D015870:Gene Expression; D005786:Gene Expression Regulation; D011905:Genes, ras; D005822:Genetic Vectors; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics / Q000378:metabolism; D017232:Oncogene Proteins v-mos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D014162:Transfection; D014316:Tritium
D017232:Oncogene Proteins v-mos; D012333:RNA, Messenger; D014316:Tritium; D003907:Dexamethasone; D003094:Collagen; D015688:Oncogene Protein pp60(v-src); D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D015689:Oncogene Protein p21(ras)