Recessive mutations in a common pathway block thymocyte apoptosis induced by multiple signals.
The glucocorticoid receptor (GR) is a ligand-regulated transcription factor that controls genes necessary to initiate glucocorticoid-induced thymocyte apoptosis. We have performed a genetic analysis of thymocyte cell death by isolating and characterizing a panel of GR+ dexamethasone-resistant mutants of the murine WEHI7.2 thymocyte cell line. These apoptosis-defective (Apt-) mutants were used to identify previously unknown early steps in the apoptotic pathway. The Apt- mutants contain nonglucocorticoid receptor, recessive mutations in genes that represent multiple complementation groups. These mutations block apoptosis induced by dexamethasone, gamma irradiation, and c-AMP treatment before the point where Bcl-2 exerts its protective effect. We propose that different signals share a common apoptotic pathway, and that the induction of apoptosis involves multiple precommitment steps that can be blocked by recessive mutations.
Flomerfelt
F A
FA
Department of Molecular and Cellular Biology, University of Arizona, Tucson 85724.
Miesfeld
R L
RL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005720:Gamma Rays; D018628:Gene Dosage; D015870:Gene Expression; D005816:Genetic Complementation Test; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011965:Receptors, Glucocorticoid; D000001:Calcimycin; D003907:Dexamethasone; D006861:Hydrogen Peroxide; D000242:Cyclic AMP