Cited by 20Cell death mechanisms and regulationProtein Kinase Regulation and GTPase SignalingNF-κB Signaling Pathways

Selective Activation of Ha-rasval12Oncogene Increases Susceptibility of NIH/3T3 Cells to TNF-α

Chang, Meng-Yao, Won, Shen-Jeu, Yang, Bei-Chang, Jan, Ming-Shiou, Liu, Hsiao-Sheng·1999·Experimental Cell Research

Abstract

This is the first report demonstrating that NIH/3T3 fibroblasts utilize the Raf-1/MAPK pathway to sensitize themselves to tumor necrosis factor-alpha (TNF-alpha) cytotoxicity under Ha-rasVal12 oncogene-overexpressed conditions. This paper clearly shows that the sensitivity of NIH/3T3 cells to TNF-alpha cytotoxicity positively correlated with the expression level of activated Ha-ras transgene, which was manipulated either positively by isopropyl-beta-d-thiogalactoside (IPTG) induction or negatively by a ribozyme or a dominant negative Ras suppression. Further analysis revealed that after TNF-alpha 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-alpha, indicating that Raf-1, as a proapoptotic factor, indeed participates in TNF-alpha 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-alpha while overexpressing Bcl-2 or the activated p110 catalytic subunit. The analyses of the cell cycle and nuclear transcription factor activities revealed that TNF-alpha 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 sen…

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Crossref · 10.1006/excr.1999.4436

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Authors
Chang, M.-Y., Won, S.-J., Yang, B.-C., Jan, M.-S., & Liu, H.-S.
Affiliations
National Cheng Kung University (TW)
Corresponding author
Liu, Hsiao-Sheng
Venue
Experimental Cell Research
Publisher
Elsevier BV
Published
1999-05
Volume
248
Issue
2
Pages
589-598
ISSN
0014-4827 (ISSN-L)
OpenAlex
W1971946381
Cited by
20
References
48
FWCI
0.80
Type
journal article
Language
en
Open access
closed
Locations
  • Experimental Cell Research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords
TNF-α, TNF-alpha cytotoxicity, Raf-1, MAPK signaling, apoptosis, NIH3T3 cells, Rac1, RhoA, Bcl-2, PI3-kinase, cell cycle arrest, AP-1, c-fos, c-Myc
MeSH terms
Dose-Response Relationship, Drug, Gene Expression Regulation, Humans, Genes, ras, Transformation, Genetic, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha, Signal Transduction, Proto-Oncogene Proteins c-myc, Proto-Oncogene Proteins c-fos, Apoptosis, Calcium-Calmodulin-Dependent Protein Kinases, ras Proteins, Transcription Factor AP-1, Transgenes, Proto-Oncogene Proteins c-raf, Inhibitory Concentration 50

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