Sensitizing effects of cadmium on TNF-alpha- and TRAIL-mediated apoptosis of NIH3T3 cells with distinct expression patterns of p53.
Tumor necrosis factor (TNF)-alpha and TNF-related apoptosis inducing ligand (TRAIL) share a common signaling pathway. Here we show a novel potentiating effect of cadmium on TNF-alpha- or TRAIL-mediated cell death via distinct signaling. TNF-alpha or TRAIL sensitized otherwise resistant NIH3T3 embryo fibroblast cells to death, when exposed to cadmium. The potentiating effects elicited by TNF-alpha or TRAIL on cell death were NF-kappaB- and SAPK/JNK-independent and were not diminished by the expression of Bcl-2. TNF-alpha potentiated the cadmium-induced accumulation of p53 but did not affect expression levels of Bax, Mdm2 and p21(WAF/CIP). A similar pattern of p53 accumulation was also observed in Balbc/3T3 fibroblasts but not in human tumor cell lines, MCF7 and HeLa cells. The synergistic cell death evoked by TNF-alpha and cadmium was attenuated by transient expression of a dominant negative p53(Val135) mutant in NIH3T3 cells and was not observed in p53(-/-) mouse embryo fibroblasts, indicating that p53 accumulation appears to contribute to cell death. In contrast, TRAIL did not further increase the cadmium-induced accumulation of p53 despite its potentiation effects on the cadmium-induced cell death. Expression of p53(Val135) mutant did not reduce TRAIL- and cadmium-mediated cell death. Taken together, these results suggest that TNF-alpha and TRAIL potentiate the cadmium-mediated cell death via distinct p53 expression patterns.
Department of Life Science, Kwangju Institute of Science and Technology, 1 Oryong-dong Puk-gu, Kwangju 500-712, Korea.
Byung Ju
BJ
Kim
Mi-Suk
MS
Kim
Ki-Bae
KB
Kim
Ki-Woo
KW
Kim
Yeon-Mi
YM
Hong
In-Ki
IK
Kim
Han-Woong
HW
Lee
Yong-Keun
YK
Jung
D016475:3T3 Cells; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002104:Cadmium / Q000494:pharmacology*; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects*; D048031:JNK Mitogen-Activated Protein Kinases; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D047888:Receptors, Tumor Necrosis Factor, Type I; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D002104:Cadmium; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases