RECESSIVE MUTATIONS IN A COMMON PATHWAY BLOCK THYMOCYTE APOPTOSIS INDUCED BY MULTIPLE SIGNALS

The glucocorticoid receptor (GR) is a ligand-regulated transcription f actor that controls genes necessary to initiate glucocorticoid-induced thymocyte apoptosis. We have performed a genetic analysis of thymocyt e cell death by isolating and characterizing a panel of GR(+) dexameth asone-resistant mutants of the murine WEHI7.2 thymocyte cell line. The se apoptosis-defective (Apt(-)) mutants were used to identify previous ly unknown early steps in the apoptotic pathway. The Apt(-) mutants co ntain nonglucocorticold receptor, recessive mutations in genes that re present multiple complementation groups. These mutations block apoptos is induced by dexamethasone, gamma irradiation, and c-AMP treatment be fore the point where Bcl-2 exerts its protective effect. We propose th at different signals share a common apoptotic pathway, and that the in duction of apoptosis involves multiple precommitment steps that can be blocked by recessive mutations.