Opposite role of Ras in tumor necrosis factor-alpha-induced cell cycle regulation: competition for Raf kinase.
Ras, a well-known oncogene, induces cell cycle stimulation through the Raf/Erk pathway and leads to cellular transformation, accompanied by other oncogenes such as c-myc and viral oncogenic protein. Here we suggest the interfering role of Ras in tumor necrosis factor (TNF)-alpha-induced cell cycle regulation. In TSU-Pr1 and T24 (oncogenic Ras cell lines), TNF-alpha suppresses cell cycle progression without induction of apoptosis, whereas AGS (wild-type Ras) is stimulated in its cell cycle by TNF-alpha coupled with activation of Erk. However, in TSU-Pr1 and T24, TNF-alpha leads to dephosphorylation of Erk1/2. Inhibition or activation of Ras can restore or convert TNF-alpha-induced cell cycle regulation in the cell lines containing the oncogenic Ras (TSU-Pr1 and T24) or AGS, respectively. Regulation of Erk also shows the coincidental pattern. We suggest the competition between the Ras pathway and TNF signaling for the binding to Raf, a common downstream target, as the cause of such reciprocal response, based on co-immunoprecipitation (co-IP) with antibodies against Raf and Ras or cellular Flice-inhibitory protein (c-FLIP), which have been recently identified upstream of Raf in death-ligand-induced cell cycle stimulation. Overexpression of Raf in TSU-Pr1, to reduce the competition, overcomes TNF-induced cell cycle arrest, also supporting our hypotheses.
Park
S J
SJ
Department of Cancer Research, National Institute of Health, Seoul, Republic of Korea.
Kim
Y Y
YY
Lim
J Y
JY
Seo
G J
GJ
Kim
J
J
Park
S I
SI
Park
B J
BJ
D001667:Binding, Competitive; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; D002453:Cell Cycle / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D014409:Tumor Necrosis Factor-alpha; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)