Selective activation of Ha-ras(Val12) oncogene increases susceptibility of NIH/3T3 cells to TNF-α

Meng Yao Chang, Shen Jeu Won, Bei Chang Yang, Ming Shiou Jan, Hsiao Sheng Liu

研究成果: Article同行評審

18 引文 斯高帕斯(Scopus)

摘要

This is the first report demonstrating that NIH/3T3 fibroblasts utilize the Raf-1/MAPK pathway to sensitize themselves to tumor necrosis factor-α (TNF-α) cytotoxicity under Ha-ras(Val12) oncogene-overexpressed conditions. This paper clearly shows that the sensitivity of NIH/3T3 cells to TNF-α cytotoxicity positively correlated with the expression level of activated Ha- ras transgene, which was manipulated either positively by isopropyl-β-D- thiogalactoside (IPTG) induction or negatively by a ribozyme or a dominant negative Ras suppression. Further analysis revealed that after TNF-α treatment, Ha-ras-overexpressed transformants underwent apoptosis. Overexpression of dominant negative Raf-1, Rac1, or RhoA in the Ha-ras transformants clarified that among these factors, only dominant negative Raf- 1 could reverse the cell sensitivity to TNF-α, indicating that Raf-1, as a proapoptotic factor, indeed participates in TNF-α cytotoxicity. The anti- apoptotic roles of Bcl-2 and PI(3) kinase are also demonstrated by the Ha-ras transformants which became more resistant to TNF-α while overexpressing Bcl- 2 or the activated p110 catalytic subunit. The analyses of the cell cycle and nuclear transcription factor activities revealed that TNF-α treatment caused the Ha-ras overexpressed transformants to shift from S to G0/G1 phase and increased the responses of AP-1, c-fos, and c-myc. Taken together, we suggest that the possible action of Ha-ras overexpression to sensitize TNF-α-treated fibroblasts is predominantly through the Ras/Raf-1/MAPK pathway to increase the responses of AP-1, c-fos, and c-myc, which are possibly involved in the aberration of cell cycle machinery, and subsequently to turn on the death pro- gram.

原文English
頁(從 - 到)589-598
頁數10
期刊Experimental Cell Research
248
發行號2
DOIs
出版狀態Published - 1999 五月 1

All Science Journal Classification (ASJC) codes

  • Cell Biology

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