Up-regulation of glutathione biosynthesis in NIH3T3 cells transformed with the ETV6-NTRK3 gene fusion.
The ETV6-NTRK3 gene fusion, first identified in the chromosomal translocation in congenital fibrosarcoma, encodes a chimeric protein tyrosine kinase with potent transforming activity. ETV6-NTRK3-dependent transformation involves the joint action of NTRK3 signaling pathways, and aberrant cell cycle progression resulting from activation of Mek1 and Akt. The level of glutathione (GSH) was found to be markedly increased in ETV6-NTRK3-transformed NIH3T3 cells. The activities of the two GSH biosynthetic enzymes as well as of glutathione peroxidase, together with their mRNAs, were also higher in the transformed cells. The transformed cells were able to grow in the presence of GSH-depleting agents, whereas the control cells were not. L-Buthionine-(S,R)-sulfoximine (BSO) inhibited activation of Mek1 and Akt in the transformed NIH3T3 cells. These observations imply that up-regulation of GSH biosynthesis plays a central role in ETV6-NTRK3-induced transformation.
Kim
Su-Jung
SJ
Division of Life Sciences, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Korea.
Kim
Hong-Gyum
HG
Lim
Hye-Won
HW
Park
Eun-Hee
EH
Lim
Chang-Jin
CJ
D000818:Animals; D019677:Artificial Gene Fusion; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002472:Cell Transformation, Viral; D004268:DNA-Binding Proteins / Q000235:genetics*; D005354:Fibrosarcoma / Q000151:congenital / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis*; D005979:Glutathione Peroxidase / Q000378:metabolism; D005981:Glutathione Synthase / Q000378:metabolism; D008298:Maleates / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets; D020812:Receptor, trkC / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D014178:Translocation, Genetic; D015854:Up-Regulation; D000097764:ETS Translocation Variant 6 Protein
D019328:Buthionine Sulfoximine; D004268:DNA-Binding Proteins; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D005979:Glutathione Peroxidase; D005981:Glutathione Synthase; D008298:Maleates; D009687:Nuclear Proteins; D050783:Proto-Oncogene Proteins c-ets; D020812:Receptor, trkC; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C014476:diethyl maleate