Interference with gene expression induces rapid apoptosis in p53-null T lymphoma cells.
Two p53-null T lymphoma cell lines proved to be highly sensitive to inhibition of gene expression. With either actinomycin D or cycloheximide, apoptosis commenced within 2 h, as indicated by loss of membrane integrity, degradation of certain proteins (including the phosphatase calcineurin) and DNA fragmentation. These effects were ablated by co-expression of Bcl-2 or co-incubation with the caspase inhibitor Z-VAD-fmk. These results suggest that the apoptotic machinery is in place in these cells but held in check by an unknown labile protein, which probably acts upstream of Bcl-2. Although cycloheximide can activate the JNK or p38 MAP kinases in some cells, neither was implicated here. However, disruption of phosphoinositide 3-kinase signaling may be involved, because the cells were also sensitive to wortmannin. The high sensitivity of the p53-null lymphoma cells to inhibitors of gene expression suggests that such inhibitors might prove useful in the cytotoxic therapy of certain tumors.
Ofir
R
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The Walter and Eliza Hall Institute of Medical Research, Post Office, Royal Melbourne Hospital, Victoria 3050 Australia.
Zhang
L C
LC
Adams
J M
JM
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D048031:JNK Mitogen-Activated Protein Kinases; D016399:Lymphoma, T-Cell / Q000188:drug therapy*; D051379:Mice; D008817:Mice, Mutant Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D048051:p38 Mitogen-Activated Protein Kinases
D000590:Amino Acid Chloromethyl Ketones; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D003609:Dactinomycin; D003513:Cycloheximide; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases